Publication
Millischer AE, Marcellin L, Santulli P, Maignien C, Bourdon M, Borghese B, Goffinet F, Chapron C
• 10/2019
OBJECTIVE: To compare the magnetic resonance imaging (MRI) features of deep infiltrating endometriosis (DIE) lesions before and after pregnancy. DESIGN: Retrospective study. SETTING: A single French university tertiary referral hospital. PATIENTS: Twenty-one women without a prior history of surgery for endometriosis with a radiological diagnosis by MRI with two sets of examinations performed before and after pregnancy. INTERVENTIONS: The volumes of the lesions were compared using the same protocol before and after pregnancy based on MRI (1.5 T) examinations by a single experienced radiologist who is a referring practitioner for image-based diagnosis of endometriosis. MAIN OUTCOME MEASURE(S): The DIE lesion volume. MEASUREMENTS AND MAIN RESULTS: Between October 2012 and December 2016, a total of 21 patients (67 lesions) were included and compared before and after pregnancy. The mean time interval between the MRI before pregnancy and delivery was 19.6 ± 8.5 months (median: 17.6, IQR 13.5-25.2 months). The mean time interval between delivery and the MRI after pregnancy was 11.0 ± 6.4 months (median: 8.3, IQR 6-15.2 months). The mean overall DIE lesion volume by MRI was significantly higher before pregnancy compared to after pregnancy (2,552 ± 3,315 mm3 vs. 1,708 ± 3,266 mm3, respectively, p < 0.01). The mean volume by MRI of the largest lesion of each patient was significantly higher before pregnancy compared to after pregnancy (4,728 ± 4,776 mm3 vs. 3165 ± 5299 mm3; p < 0.01). CONCLUSION: Our data indicate a favorable impact of pregnancy on DIE lesion volumes as measured by MRI.
Publication
Bourdon M, Santulli P, Chen Y, Patrat C, PocateCheriet K, Maignien C, Marcellin L, Chapron C
• 09/2019
OBJECTIVE: The aim of this study was to assess whether a deferred frozen-thawed embryo transfer (Def-ET) offers any benefits compared to a fresh ET strategy in women who have had 2 or more consecutive in vitro fertilization (IVF)/intracytoplasmic injection (ICSI) cycle failures. DESIGN: An observational cohort study in a tertiary referral care center including 416 cycles from women with a previous history of 2 or more consecutive IVF/ICSI failures cycles. Both Def-ET and fresh ET strategies were compared using univariate and multivariate logistic regression models. The main outcome measured was the cumulative live birth rate (CLBR). RESULTS: A total of 416 cycles were included in the analysis: 197 in the fresh ET group and 219 in the Def-ET group. The CLBR was not significantly different between the fresh and Def-ET groups (58/197 [29.4%] and 57/219 [26.0%], respectively, P = .437). In addition, after the first ET, there was no significant difference in the live birth rate between the fresh ET and Def-ET groups (50/197 [25.4%] vs 44/219 [20.1%], respectively). Multivariate logistic regression analysis indicated that compared to the fresh strategy, the Def-ET strategy was not associated with a higher probability of live birth. CONCLUSIONS: In cases with 2 or more consecutive prior IVF/ICSI cycle failures, a Def-ET strategy did not result in better ART outcomes than a fresh ET strategy.
Publication
Marcellin L, Santulli P, Pinzauti S, Bourdon M, Lamau MC, Borghese B, Petraglia F, Chapron C
• 07/2019
OBJECTIVE: To evaluate the association between the endometriosis phenotype and the age at menarche. DESIGN: An observational, cross-sectional study using prospectively collected data (Canadian Task Force classification II-2). SETTING: Single university tertiary referral center. PATIENTS: To be eligible, women had to have undergone their 1st complete surgical exeresis of endometriotic lesions. For each patient, a standardized questionnaire was completed the month before the surgery. Endometriotic lesions were classified into 3 phenotypes: superficial peritoneal endometriosis (SUP), endometrioma (OMA), or deep infiltrating endometriosis (DIE). Patients were divided into 3 groups: early menarche (< 12 years), typical menarche (≥ 12 and ≤ 13 years) and late menarche (> 13 years). The groups were compared in terms of general characteristics, medical history, disease phenotype, and disease severity. INTERVENTIONS: Surgical management for a benign gynecologic condition. MAIN OUTCOME MEASURE(S): Correlation between the endometriosis phenotype and the age at menarche. MEASUREMENTS AND MAIN RESULTS: From January 2004 to December 2016, 789 women with histologically confirmed endometriosis were enrolled in the study. The mean age at menarche was 12.9 ± 1.6 years of age, (range 9 to 18). The mean age at menarche and the mean time interval between menarche and the 1st surgery for endometriosis were not significantly different between the three phenotypes (SUP, OMA, DIE). When women with early menarche, typical menarche, or late menarche were compared, no differences were observed in terms of the endometriosis phenotype and the anatomical distribution of the endometriotic lesions. CONCLUSION: For women operated for the first time for endometriosis, age at menarche is not associated with the disease phenotype.
Publication
Riccio LGC, Jeljeli M, Santulli P, Chouzenoux S, Doridot L, Nicco C, Reis FM, Abrão MS, Chapron C, Batteux F
• 07/2019
STUDY QUESTION: What are the effects of B lymphocyte inactivation or depletion on the progression of endometriosis? SUMMARY ANSWER: Skewing activated B cells toward regulatory B cells (Bregs) by Bruton's tyrosine kinase (Btk) inhibition using Ibrutinib prevents endometriosis progression in mice while B cell depletion using an anti-CD20 antibody has no effect. WHAT IS KNOWN ALREADY: A polyclonal activation of B cells and the presence of anti-endometrial autoantibodies have been described in a large proportion of women with endometriosis though their exact role in the disease mechanisms remains unclear. STUDY DESIGN, SIZE, DURATION: This study included comparison of endometriosis progression for 21 days in control mice versus animals treated with the anti-CD20 depleting antibody or with the Btk inhibitor Ibrutinib that prevents B cell activation. PARTICIPANTS/MATERIALS, SETTING, METHODS: After syngeneic endometrial transplantation, murine endometriotic lesions were compared between treated and control mice using volume, weight, ultrasonography, histology and target genes expression in lesions. Phenotyping of activated and regulatory B cells, T lymphocytes and macrophages was performed by flow cytometry on isolated spleen and peritoneal cells. Cytokines were assayed by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Btk inhibitor Ibrutinib prevented lesion growth, reduced mRNA expression of cyclooxygenase-2, alpha smooth muscle actin and type I collagen in the lesions and skewed activated B cells toward Bregs in the spleen and peritoneal cavity of mice with endometriosis. In addition, the number of M2 macrophages decreased in the peritoneal cavity of Ibrutinib-treated mice compared to anti-CD20 and control mice. Depletion of B cells using an anti-CD20 antibody had no effect on activity and growth of endometriotic lesions and neither on the macrophages, compared to control mice. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: It is still unclear whether B cell depletion by the anti-CD20 or inactivation by Ibrutinib can prevent establishment and/or progression of endometriosis in humans. WIDER IMPLICATIONS OF THE FINDINGS: Further investigation may contribute to clarifying the role of B cell subsets in human endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant of Institut National de la Santé et de la Recherche Médicale and Paris Descartes University. None of the authors has any conflict of interest to disclose.
Publication
Peyneau M, Kavian N, Chouzenoux S, Nicco C, Jeljeli M, Toullec L, ReboulMarty J, ChenevierGobeaux C, Reis FM, Santulli P, Doridot L, Chapron C, Batteux F
• 06/2019
Endometriosis is characterized by the presence of ectopic endometrial cells outside the uterine cavity. Thyroid autoimmunity has been associated with endometriosis. This work investigated the potential pathophysiological link between endometriosis and thyroid disorders. Transcripts and proteins involved in thyroid metabolism are dysregulated in eutopic and ectopic endometrium of endometriotic patients, leading to resistance of ectopic endometrium to triiodothyronine (T3) action and local accumulation of thyroxine (T4). Thyroid-stimulating hormone (TSH) acts as a proliferative and prooxidative hormone on all endometria of endometriosis patients and controls, whereas T3 and T4 act to specifically increase ectopic endometrial cell proliferation and reactive oxygen species (ROS) production. Mouse studies confirmed the data gained in vitro since endometriotic implants were found to be bigger when thyroid hormones increased. A retrospective analysis of endometriosis patients with or without a thyroid disorder revealed an increased chronic pelvic pain and disease score in endometriotic patients with a thyroid disorder.
Publication
Marcellin L, Santulli P, Bourdon M, Comte C, Maignien C, Just PA, Streuli I, Borghese B, Chapron C
• 05/2019
OBJECTIVE: To examine whether serum antimüllerian hormone (AMH) levels correlate with the size of ovarian endometrioma (OMA). DESIGN: An observational cross-sectional study. SETTING: University hospital. PATIENT(S): Two hundred and sixty-seven nonpregnant women, aged 18-42 years, with no prior history of surgery for endometriosis and a histologically documented ovarian cyst. INTERVENTION(S): Surgical management for a benign ovarian cyst. MAIN OUTCOME MEASURE(S): Correlation between serum AMH concentration and cyst size according to OMA and non-OMA benign cyst. RESULT(S): Women with OMA were compared with a control group of women who had non-OMA benign ovarian cysts. The AMH assay samples were collected less than a month before the surgery. Between January 2004 and September 2016, 148 women were allocated to the OMA group and 119 to the non-OMA benign cyst group. The AMH concentrations were not statistically significantly different between the two groups (3.7 ± 2.8 ng/mL vs. 4.1 ± 3.3 ng/mL). A multiple linear regression model accounting for potential confounders revealed that the log10 of the serum AMH concentration positively correlated with the log10 of the OMA cyst volume (R2 = 0.23; coefficient = 0.05; 95% CI, 0.007-0.10). CONCLUSION(S): In women no prior history of surgery for endometriosis, serum AMH levels increased with cyst size in cases of OMA.
Publication
Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, Missmer SA, Singh SS, Taylor HS
• 04/2019
Endometriosis can have a profound impact on women's lives, including associated pain, infertility, decreased quality of life, and interference with daily life, relationships, and livelihood. The first step in alleviating these adverse sequelae is to diagnose the underlying condition. For many women, the journey to endometriosis diagnosis is long and fraught with barriers and misdiagnoses. Inherent challenges include a gold standard based on an invasive surgical procedure (laparoscopy) and diverse symptomatology, contributing to the well-established delay of 4-11 years from first symptom onset to surgical diagnosis. We believe that remedying the diagnostic delay requires increased patient education and timely referral to a women's healthcare provider and a shift in physician approach to the disorder. Endometriosis should be approached as a chronic, systemic, inflammatory, and heterogeneous disease that presents with symptoms of pelvic pain and/or infertility, rather than focusing primarily on surgical findings and pelvic lesions. Using this approach, symptoms, signs, and clinical findings of endometriosis are anticipated to become the main drivers of clinical diagnosis and earlier intervention. Combining these factors into a practical algorithm is expected to simplify endometriosis diagnosis and make the process accessible to more clinicians and patients, culminating in earlier effective management. The time has come to bridge disparities and to minimize delays in endometriosis diagnosis and treatment for the benefit of women worldwide.
Publication
Maignien C, Santulli P, Chouzenoux S, GonzalezForuria I, Marcellin L, Doridot L, Jeljeli M, Grange P, Reis FM, Chapron C, Batteux F
• 03/2019
STUDY QUESTION: Is endometriosis associated with aberrant sialylation patterns and what is the potential impact of such anomalies on cell migratory properties? SUMMARY ANSWER: The reduced α-2,6 sialylation patterns in the peritoneal fluid of endometriosis-affected women and in stromal and epithelial cells from endometriotic lesions could be associated with enhanced cell migration. WHAT IS KNOWN ALREADY: Endometriosis is considered to be a benign disease although, like cancer, it has the characteristic of being an invasive disease with cells that have an enhanced capacity to migrate. Aberrant sialylation has been reported in various malignancies and it has been linked to tumour invasion and metastasis. STUDY DESIGN, SIZE, DURATION: We conducted a prospective laboratory study in a tertiary-care university hospital. We investigated non-pregnant patients who were <42 years of age (n = 273) when they underwent surgery for a benign gynaecological condition. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population consisted of 102 women with histologically proven endometriosis and 71 endometriosis-free controls, who underwent a complete surgical exploration of the abdominopelvic cavity. Peritoneal fluids were collected during the surgical procedures, and endometrial and endometriotic biopsies were performed on all of the patients to generate stromal and epithelial primary cell cultures. The expression of α-2,6-sialyltransferase (ST6GALNAC1) was studied in eutopic and ectopic endometria of endometriosis patients and in eutopic endometria of controls by reverse transcription followed by quantitative real-time polymerase chain reaction (RT-qPCR). The α-2,6 sialylation levels were measured by ELISA in the peritoneal fluids of patients and controls and by western-blot in primary endometrial and endometriotic cell cultures using Sambucus nigra agglutinin (SNA), an α-2,6 sialic acid-binding lectin. A transwell migration assay after incubation of the cells with neuraminidase was also performed to evaluate the impact of desialylation on eutopic endometrial stromal cell migration. MAIN RESULTS AND THE ROLE OF CHANCE: ST6GALNAC1 gene expression was significantly lower in endometriotic lesions compared to that in eutopic endometrium of endometriosis-affected patients and healthy endometrium (16-fold for both; P < 0.01). We observed a significant reduction in SNA levels in the peritoneal fluids of endometriosis-affected women compared to control women (median optic density (OD), 0.257; range, 0.215-0.279 versus median OD, 0.278; range 0.238-0.285; P < 0.01), as well as in stromal (mean OD, 705 907; standard error of the mean (SEM), 141 549 versus mean OD, 1.16 × 106; SEM, 107,271; P < 0.05) and epithelial (mean OD, 485 706; SEM, 179 681 versus mean OD, 1.25 × 106; SEM, 232 120; P < 0.05) ectopic endometriotic cells compared to control eutopic cells, indicating reduced α-2,6 sialylation. Finally, in the transwell migration assay, the eutopic endometrial cells of endometriosis patients migrated significantly more into the lower chamber after incubation with neuraminidase, indicating enhanced migration by these cells after desialylation. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Our control group involved patients operated for benign gynaecological conditions (e.g. tubal infertility, uterine fibroids or ovarian cysts) which may also be associated with altered sialylation patterns. WIDER IMPLICATIONS OF THE FINDINGS: The hyposialylation pattern of endometriotic cells appeared to be associated with enhanced migratory abilities, which might contribute to the establishment of early endometriotic implants. Further research is needed to confirm these findings, as this could lead to new potential therapeutic targets for this complex disorder. STUDY FUNDING AND COMPETING INTEREST(S): No external funding was received and there are no conflicts of interest.
Publication
Bourdon M, Santulli P, Chouzenoux S, Maignien C, Bailly K, Andrieu M, Millischer AE, Doridot L, Marcellin L, Batteux F, Chapron C
• 02/2019
BACKGROUND: Adenomyosis (ADE) is an enigmatic uterine disorder. Several types have been previously described: diffuse adenomyosis (DIF-ADE), focal adenomyosis (FOC-ADE), and association of focal and diffuse lesions (FOC/DIF-ADE). Abnormal immune phenomena have been described that may provide an understanding of the pathophysiology of adenomyosis. However, the immune imbalance in adenomyosis is however still poorly understood. OBJECTIVE: To compare serum cytokine profiles for the various adenomyosis phenotypes in adenomyosis versus disease-free women. MATERIALS AND METHODS: This cohort study included 80 women. Based on the magnetic resonance imaging (MRI) findings, the women were allocated to the ADE group (n = 60) and the control group (n = 20). The ADE group was further subdivided according to the phenotype: DIF-ADE, FOC-ADE, and FOC/DIF-ADE. For all of the women, serum cytokine levels were assayed by multiplex immunoassay. RESULTS: Serum levels of interleukin (IL) 23 (237.77 pg/mL ± 70.97 in the ADE-group versus 1855.04 ± 1411.33 in the control group, P = .019), IL25 (31.98 ± 8.54 vs 222.08 ± 170.90, respectively, P = .006), IL31 (10.13 ± 3.83 vs 91.51 ± 71.21, respectively, P = .034), IL33 (3.77 ± 1.23 vs 17.86 ± 11.49, respectively, P = .016), and IL17F (16.29 ± 2.35 vs 30.12 ± 8.29, respectively, P = .042) were significantly lower in the women with adenomyosis when compared to the controls In the FOC/DIF-ADE group, the serum levels of IL23, IL31, IL25, and IL33 were significantly lower when compared to the control group. CONCLUSION: Serum levels of IL23, IL31, IL25, and IL33 were lower in women exhibiting adenomyosis forms with associated diffuse and focal lesions when compared with controls. The pathogenesis of adenomyosis may be associated with an immunotolerant process that is more pronounced in associated FOC/DIF-ADE.
