Publication
Santulli P, Lamau MC, Marcellin L, Gayet V, Marzouk P, Borghese B, Lafay Pillet MC, Chapron C
• 08/2016
STUDY QUESTION: Is there an association between the endometriosis phenotype and presentation with infertility? SUMMARY ANSWER: In a population of operated patients with histologically proven endometriosis, ovarian endometrioma (OMA) per se is not associated with an increased risk of presentation with infertility, while previous surgery for endometriosis was identified as a risk factor for infertility. WHAT IS KNOWN ALREADY: The increased prevalence of endometriosis among subfertile women indicates that endometriosis impairs reproduction for reasons that are not completely understood. STUDY DESIGN, SIZE, DURATION: This was an observational, cross-sectional study using data prospectively collected in all non-pregnant patients aged between 18 and 42 years, who were surgically explored for benign gynaecological conditions at our institution between January 2004 and March 2013. For each patient, a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: Surgery was performed in 2208 patients, of which 2066 signed their informed consent. Of the 1059 women with a visual diagnosis of endometriosis, 870 had histologically proven endometriosis and complete treatment for their endometriotic lesions, including 307 who presented with infertility. Univariate analysis and multiple logistic regression analysis were performed to determine factors associated with infertility. MAIN RESULTS AND THE ROLE OF CHANCE: The following variables were identified as risk factors for endometriosis-related infertility: age >32 years (odds ratio [OR] = 1.9; 95% confidence interval [CI]: 1.4-2.4), previous surgery for endometriosis (OR = 1.9; 95% CI: 1.3-2.2), as well as peritoneal superficial endometriosis (OR = 3.1; 95% CI: 1.9-4.9); Conversely, previous pregnancy was associated with a lower rate of infertility (OR = 0.7; 95% CI: 0.6-0.9 and OR = 0.6; 95% CI: 0.4-0.9, respectively). OMA is not selected as a significant risk factor for infertility. LIMITATIONS, REASON FOR CAUTION: The selection of our study population was based on a surgical diagnosis. We cannot exclude that infertile women with OMA associated with a diminished ovarian reserve, as assessed during their infertility work-up, were referred less frequently to surgery and might therefore be underrepresented. In addition we cannot exclude that our group of infertile women present associated other causes of infertility. WIDER IMPLICATIONS OF THE FINDINGS: Identification of risk and preventive factors of endometriosis-related infertility can help improve clinical and surgical management of endometriosis in the setting of infertility. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: None.
Publication
Thubert T, Foulot H, Vinchant M, Santulli P, Marzouk P, Borghese B, Chapron C
• 07/2016
Uterine fibroids affect 25% of women worldwide. Symptomatic women can be treated by either medical or surgical treatment. Development of endoscopic surgery has widely changed the management of myoma. Currently, although laparoscopic or laparoscopic robot-assisted myomectomies or hysterectomies are common, there has been no consensual guideline concerning the surgical techniques, operative route, and usefulness of preoperative treatment. Hysteroscopy management is a major advancement avoiding invasive surgery. This study deals with a literature review concerning surgical management of fibroids.
Publication
Vanhie A, Meuleman C, Tomassetti C, Timmerman D, D'Hoore A, Wolthuis A, Van Cleynenbreugel B, Dancet E, Van den Broeck U, Tsaltas J, Renner SP, Ebert AD, Carmona F, Abbott J, Stepniewska A, Taylor H, Saridogan E, Mueller M, Keckstein J, Pluchino N, Janik G, Zupi E, Minelli L, Cooper M, Dunselman G, Koh C, Abrao MS, Chapron C, D'Hooghe T
• 06/2016
STUDY QUESTION: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION: International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER: N/A.
Publication
Santulli P, Marcellin L, Menard S, Thubert T, Khoshnood B, Gayet V, Goffinet F, Ancel PY, Chapron C
• 05/2016
STUDY QUESTION: Were spontaneous miscarriages more frequent in women with histologically proven endometriosis when compared with endometriosis-free controls? SUMMARY ANSWER: Endometriosis-affected women display a significantly higher rate of previous spontaneous miscarriages than endometriosis-free controls. WHAT IS KNOWN ALREADY: The association between endometriosis and miscarriages has long been debated without reaching a consensus. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study comparing exposed women (endometriosis) and control (without endometriosis) regarding the incidence of miscarriages. All study participants underwent surgery for benign gynaecological conditions in a tertiary-care university hospital between January 2004 and March 2013. After thorough surgical examination of the abdominopelvic cavity, 870 women with histologically proven endometriosis were allocated to the endometriosis group and 981 unaffected women to the control group. Only previously pregnant women were finally included for the study analysis: 284 women in the endometriosis group and 466 in the control group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected preoperatively using a structured questionnaire. Among women with at least one pregnancy before the surgery, the type and number of the different previous first trimester pregnancies outcomes were studied. Previous history of miscarriage was studied according to the existence of previous infertility history and the disease severity (revised American Fertility Society and surgical classification). MAIN RESULTS AND THE ROLE OF CHANCE: Four hundred and seventy-eight pregnancies in endometriosis-affected women and 964 pregnancies in controls were analysed. The previous miscarriage rate was significantly higher in women with endometriosis compared with the controls (139/478 [29] versus 187/964 [19%], respectively; ITALIC! P < 0.001). After a subgroup analysis, the miscarriage rates of women with endometriosis and the controls were, respectively: 20 versus 12% ( ITALIC! P = 0.003) among women without a previous history of infertility and 53 versus 30% ( ITALIC! P < 0.001) for women with a previous history of infertility. After using a random-effects Poisson regression and adjusting for confounding factors, we found a significantly increased incidence rate ratio (IRR) for miscarriages in women with endometriosis (adjusted IRR: 1.70, 95% confidence interval: 1.34-2.16). LIMITATIONS, REASONS FOR CAUTION: There is a possible selection bias due to the specificity of the study design which included only surgical patients. In the control group, certain of the surgical gynaecological conditions, such as fibroids, ovarian cysts or tubal pathologies, might be associated with higher spontaneous miscarriage rates. In the endometriosis group, asymptomatic women were less likely to be referred for surgery and might therefore be underrepresented. WIDER IMPLICATIONS OF THE FINDINGS: This study opens the doors to future, more mechanistic studies to establish the exact link between endometriosis and spontaneous miscarriage rates. STUDY FUNDING/COMPETING INTERESTS: No external funding was used for this study. The authors have no conflicts of interest to declare.
Publication
Santulli P, de Villardi D, Gayet V, Lafay Pillet MC, Marcellin L, Blanchet V, Gonnot J, Dulioust E, Launay O, Chapron C
• 04/2016
OBJECTIVE: To evaluate HIV directly or indirectly related altered ovarian function, using serum anti-Müllerian hormone (AMH) levels in HIV-infected women as compared with seronegative women. DESIGN: We conducted a matched cohort study from January 2008 to December 2013 in a tertiary university centre. Two hundred and one HIV-infected women requesting assisted reproductive technology and 603 age and cause of infertility-matched HIV seronegative women were enrolled in this study. METHODS: All data were prospectively collected using a semistructured questionnaire. Serum AMH levels in HIV-infected women and matched controls were compared. To find out the contributing factors to increased serum AMH levels in HIV-infected women, a backward multiple linear regression was performed. RESULTS: Serum AMH levels were significantly lower in HIV-infected group as compared with seronegative controls (3.0 ± 2.8 vs 3.7 ± 3.5 ng/ml; respectively, P = 0.001). Looking for factors associated with altered AMH among HIV-infected women, an association has been shown between tubal disease and a further decrease in serum AMH levels (2.4 ± 2.4 vs 3.4 ± 3.0 ng/ml; respectively, P = 0.011). Among HIV-infected women, after multivariate linear regression analysis, we showed that increased age, BMI and viral load were associated with decreased serum AMH levels whereas in striking contrast an increase in CD4⁺ cell count was associated with an increase of serum AMH levels. CONCLUSION: Serum AMH levels were lower in the HIV-infected group than in the control group. Age, BMI, CD4⁺ cell count and viral load were the independent contributors affecting serum AMH levels among HIV-infected women.
Publication
Filippi I, Carrarelli P, Luisi S, Batteux F, Chapron C, Naldini A, Petraglia F
• 04/2016
Endometriosis is associated with local angiogenic and hypoxic mechanisms. Indeed, peritoneal fluid of women with endometriosis generates a specific microenvironment to support the growth and development of ectopic endometrial tissues. The association between proangiogenic markers and hypoxic processes in different endometriosis phenotypes was investigated in the present study, analyzing the expression of several genes, related to hypoxic signaling pathway and involved in angiogenic processes, in nonpregnant women with different forms of endometriosis. Samples of ovarian endometrioma (OMA; n = 16) or deep infiltrating endometriosis (DIE; n = 11) were collected, and in addition, control endometrium was collected from healthy women by hysteroscopy. The gene expression of the hypoxia-inducible factors (HIF) 1/2α, protease-activated receptors (PARs) ¼, and vascular endothelial growth factor (VEGF) A was evaluated by quantitative reverse-transcription polymerase chain reaction. Ovarian endometrioma expresses high levels of HIF-1/2α, PAR-1/4, and VEGF-A, while DIE did not show significantly different gene expression compared to endometrium from unaffected women. A positive correlation between the expression of HIF-1/2α and VEGF-A mRNA was observed in OMA. The overall data point out that the heterogeneity of the disease reflects differences in expression levels of genes associated with hypoxia and angiogenesis, suggesting that such conditions may have an active role in the development of the disease.
Publication
Santulli P, Bourdon M, Presse M, Gayet V, Marcellin L, Prunet C, de Ziegler D, Chapron C
• 04/2016
OBJECTIVE: To evaluate the impact of assisted reproduction technology (ART) on painful symptoms and quality of life (QoL) in women who have endometriosis as compared with disease-free women. DESIGN: Prospective controlled, observational cohort study. SETTING: University hospital. PATIENT(S): Two hundred and sixty-four matched-pairs of endometriosis and disease-free women undergoing ART. INTERVENTION(S): Assessment of pain evolution using visual analogue scale (VAS) during ART; QoL assessment with the Fertility Quality of Life (FertiQoL) tool. MAIN OUTCOME MEASURE(S): VAS pain intensities relative to dysmenorrhea, dyspareunia, noncyclic chronic pelvic pain (NCCPP), gastrointestinal pain, lower urinary tract pain; trends for VAS change between postretrieval and baseline evaluation; FertiQoL score; and statistical analyses conducted using univariate and adjusted multiple linear regression models. RESULT(S): After excluding canceled cycles and patients lost to follow-up observation, 102 women with endometriosis and 104 disease-free women were retained for the study. The trends for VAS change between the postretrieval and baseline evaluations in the women with endometriosis compared with the disease-free women revealed a statistically significant pain decrease for dysmenorrhea (-1.35 ± 3.23 and 0.61 ± 4.00) and dyspareunia (-1.19 ± 2.58 and 0.14 ± 2.06). For NCCPP, gastrointestinal symptoms, and lower urinary tract symptoms, there were no statistically significant differences between the groups. After multiple linear regression, no worsening of pain was observed in the endometriosis group as compared with disease-free group. In addition subgroup analysis according to endometriosis phenotype failed to show any increase of pain. The quality of life in the endometriosis group was comparable to that of the disease-free group. CONCLUSION(S): Assisted reproduction technology did not exacerbate the symptoms of endometriosis or negatively impact QoL in women with endometriosis as compared with disease-free women.
Publication
Bouyou J, Gaujoux S, Marcellin L, Leconte M, Goffinet F, Chapron C, Dousset B
• 12/2015
Abdominal emergencies during pregnancy (excluding obstetrical emergencies) occur in one out of 500-700 pregnancies and may involve gastrointestinal, gynecologic, urologic, vascular and traumatic etiologies; surgery is necessary in 0.2-2% of cases. Since these emergencies are relatively rare, patients should be referred to specialized centers where surgical, obstetrical and neonatal cares are available, particularly because surgical intervention increases the risk of premature labor. Clinical presentations may be atypical and misleading because of pregnancy-associated anatomical and physiologic alterations, which often result in diagnostic uncertainty and therapeutic delay with increased risks of maternal and infant morbidity. The most common abdominal emergencies are acute appendicitis (best treated by laparoscopic appendectomy), acute calculous cholecystitis (best treated by laparoscopic cholecystectomy from the first trimester through the early part of the third trimester) and intestinal obstruction (where medical treatment is the first-line approach, just as in the non-pregnant patient). Acute pancreatitis is rare, usually resulting from trans-ampullary passage of gallstones; it usually resolves with medical treatment but an elevated risk of recurrent episodes justifies laparoscopic cholecystectomy in the 2nd trimester and endoscopic sphincterotomy in the 3rd trimester. The aim of the present work is to review pregnancy-induced anatomical and physiological modifications, to describe the main abdominal emergencies during pregnancy, their specific features and their diagnostic and therapeutic management.
Publication
Streuli I, Santulli P, Chouzenoux S, Chapron C, Batteux F
• 12/2015
We investigated whether the myometrium might be intrinsically different in women with adenomyosis. We studied whether the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs) and phosphoinositide 3-kinase/mammalian target of rapamycin/AKT (PI3K/mTOR/AKT) cell-signaling pathways, implicated in the pathogenesis of endometriosis, might also be activated in uterine smooth muscle cells (uSMCs) of women with adenomyosis and measured the production of reactive oxygen species (ROS), proinflammatory mediators that modulate cell proliferation and have been shown to activate the MAPK/ERK pathway in endometriosis. The uSMC cultures were derived from myometrium biopsies obtained during hysterectomy or myomectomy in women with adenomyosis and controls with leiomyoma. Proliferation of uSMCs and in vitro activation of the MAPK/ERK cell-signaling pathway were increased in women with adenomyosis compared to controls. The activation of the PI3K/mTOR/AKT pathway was not significant. The ROS production and ROS detoxification pathways were not different between uSMCs of women with adenomyosis and controls suggesting an ROS-independent activation of the MAPK/ERK pathway. Our results also provide evidence that protein kinase inhibitors and the rapanalogue temsirolimus can control proliferation of uSMCs in vitro suggesting an implication of the MAPK/ERK and the PI3K/mTOR/AKT pathways in proliferation of uSMCs in women with adenomyosis and leiomyomas.
Publication
Tosti C, Pinzauti S, Santulli P, Chapron C, Petraglia F
• 09/2015
Endometriosis is a benign gynecologic disease, affecting women of reproductive age associated with chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. Ovarian endometrioma (OMA), superficial peritoneal endometriosis (SPE), and deep infiltrating endometriosis (DIE) are, till now, recognized as major phenotypes. The discussion is to know whether they share the same pathogenetic mechanisms. Till today, DIE is recognized as the most severe clinical form of endometriosis and has a complex clinical management. The DIE lesions have been considered in the present article, without distinguishing between the anterior (bladder) or the posterior (vagina, uterosacral ligaments, rectum, and ureter) compartment. The present knowledge indicates that hormonal function (estrogen and progesterone receptors) and immunological factors, such as peritoneal macrophages, natural killer cells, and lymphocytes, are critically altered in DIE. The aggressive behavior of DIE may be explained by the highly decreased apoptosis (nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kB], B-cell lymphoma 2 [Blc-2], and anti-Mullerian hormone) and by the increased proliferation activity related to oxidative stress (NF-kB, reactive oxygen species, extracellular regulated kinase (ERK), advanced oxidation protein product). Invasive mechanisms are more expressed (matrix metalloproteinases and activins) in DIE in comparison to the OMA and SPE. Correlated with the increased invasiveness are the data on very high expression of neuroangiogenesis (nerve growth factor, vascular endothelial growth factor, and intercellular adhesion molecule) genes in DIE. Therefore, at the present time, several of the DIE pathogenetic features result specific in comparison to other endometriosis phenotypes, pleading for the existence of a specific entity. These evidence of specific pathogenetic features of DIE may explain the more severe symptomatology related to this form of endometriosis and suggest possible future target medical treatments.
