Publication
Santulli P, Borghese B, Lemaréchal H, Leconte M, Millischer AE, Batteux F, Chapron C, Borderie D
• 08/2013
BACKGROUND: Uterine leiomyomas (fibroids) are the most common gynaecological benign tumors in premenopausal women. Evidences support the role of oxidative stress in the development of uterine leiomyoma. We have analysed oxidative stress markers (thiols, advanced oxidized protein products (AOPP), protein carbonyls and nitrates/nitrites) in preoperative sera from women with histologically proven uterine leiomyoma. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a laboratory study in a tertiary-care university hospital. Fifty-nine women with histologically proven uterine leiomyoma and ninety-two leiomyoma-free control women have been enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Preoperative serum samples were obtained from all study participants to assay serum thiols, AOPP, protein carbonyls and nitrates/nitrites. Concentrations of serum protein carbonyl groups and AOPP were higher in leiomyoma patients than in the control group (p=0.005 and p<0.001, respectively). By contrast, serum thiol levels were lower in leiomyoma patients (p<0.001). We found positive correlations between serum AOPP concentrations and total fibroids weight (r=0.339; p=0.028), serum AOPP and serum protein carbonyls with duration of infertility (r=0.762; p=0.006 and r=0.683; p=0.021, respectively). CONCLUSIONS/SIGNIFICANCE: This study, for the first time, reveals a significant increase of protein oxidative stress status and reduced antioxidant capacity in sera from women with uterine leiomyoma.
Publication
Santulli P, Even M, Chouzenoux S, Millischer AE, Borghese B, de Ziegler D, Batteux F, Chapron C
• 08/2013
STUDY QUESTION: Are interleukin-33 (IL-33) serum levels higher in women with uterine leiomyoma compared with controls without leiomyoma? SUMMARY ANSWER: Serum IL-33 is elevated in women with uterine leiomyoma and correlated with features of uterine leiomyoma tumour burden, namely fibroid number, size and weight. WHAT IS KNOWN ALREADY: Uterine leiomyomas are the most common benign tumours in premenopausal women associated with major tissue fibrosis. IL-33 is a cytokine involved in fibrotic disorders. The potential role of IL-33 in leiomyoma has not been reported before. STUDY DESIGN, SIZE, DURATION: This is a prospective laboratory study conducted in a tertiary-care university hospital between January 2005 and December 2010. We investigated non-pregnant, 42-year-old patients (n = 151) during surgery for a benign gynaecological condition. PARTICIPANTS/MATERIALS, SETTING, METHODS: After complete surgical exploration of the abdominopelvic cavity, 59 women with histologically proved uterine leiomyoma and 92 leiomyoma-free control women were enrolled. Women with endometriosis or past history of ovarian malignancy and borderline tumours were not included. The control group included women with benign ovarian cysts, paratubal cysts or tubal defects without any evidence of uterine leiomyoma. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. Serum samples were obtained in the month preceding the surgical procedures according to the menstrual phase or hormonal therapy. IL-33 was measured in sera by enzyme-linked immunosorbent assay, and correlation of IL-33 concentration with the extent and severity of the disease was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: IL-33 was detected in 32 (54.2%) women with leiomyoma and 18 (19.6%) controls (P < 0.001). Serum IL-33 was higher in women with leiomyoma (median, 140.1 pg/ml; range, 7.5-2247.7) than in controls (median, 27.8 pg/ml; range, 7.5-71.6; P = 0.002). We found positive correlations between serum IL-33 concentration and leiomyoma features, such as fibroid weight (r = 0.630; P = 0.001) and size (r = 0.511; P = 0.018) and the number of fibroids (r = 0.503; P = 0.003). LIMITATIONS, REASONS FOR CAUTION: There was a possible selection bias due to inclusion of only surgical patients. Therefore our control group consisted of women who underwent surgery for benign gynaecological conditions. This may lead to biases stemming from the fact that certain of these conditions, such as tubal infertility or ovarian cysts, might be associated with altered serum IL-33 levels. WIDER IMPLICATIONS OF THE FINDINGS: We demonstrate for the first time that elevated serum IL-33 levels are associated with the existence of uterine leiomyoma. However, even if an association does not constitute proof of cause and effect, investigating the mechanisms that underlie fibrogenesis associated with leiomyomas is a step towards understanding this enigmatic disease. This study opens the doors to future, more mechanistics studies to establish the exact role of IL-33 in uterine leiomyomas pathogenesis. STUDY FUNDING/COMPETING INTEREST(S): No funding, no conflict of interest.
Publication
Borghese B, Santulli P, Vaiman D, Alexandre J, Goldwasser F, Chapron C
• 06/2013
Endometriosis is considered as a tumor-like lesion under the World Health Organization (WHO) classification of ovarian tumors. Data from large cohort and case-control studies indicate that patients with a history of endometriosis have an increased risk of ovarian cancer. Recent findings suggest an association between endometriosis and the entire type 1 ovarian tumors group including clear-cell, endometrioid and low-grade serous carcinomas. However, current evidence is lacking to draw definitive conclusion whether this association represents causality or the sharing of common risk factors. Nevertheless, assumption that endometriosis could be a precursor of malignancy raises many issues about serial screening, surgical management and surveillance of endometriosis. Beyond these concerns, endometriosis-associated ovarian cancers seem to be a genuine clinical entity as regards clinicopathological features. In view of the high incidence of endometriosis (10 % of women of childbearing age), the low incidence of endometriosis-associated ovarian cancers and the psychological consequences for those women, systematic screening and surgical exploration seem very questionable in this context.
Publication
Streuli I, de Ziegler D, Santulli P, Marcellin L, Borghese B, Batteux F, Chapron C
• 02/2013
INTRODUCTION: Endometriosis is a common disease that causes pain symptoms and/or infertility in women in their reproductive years. The disease is characterised by the presence of endometrium-like tissue - glands and stroma - outside the uterine cavity. Different treatment options exist for endometriosis including medical and surgical treatments or a combination of the two approaches. The most commonly used medications are non-steroidal anti-inflammatory drugs, GnRH agonists, androgen derivatives such as danazol, combined oral contraceptive pills, progestogens and more recently the levonorgestrel intrauterine system. AREAS COVERED: The authors review current medical treatments used for symptomatic endometriosis and also discuss new treatment approaches. The authors conducted a literature search for randomised controlled trials related to medical treatments of endometriosis in humans, searched the Cochrane library for reviews and also searched for registered trials that have not yet been published on ClinicalTrials.gov. EXPERT OPINION: The medical treatment of endometriosis is effective at treating pain and preventing recurrence of disease after surgery. Remarkably, the oral contraceptive pill taken continuously is as effective as GnRH-a, while causing far less side-effects. Conversely, no treatment currently exists for enhancing fecundity in women whose infertility is associated with endometriosis. As all existing therapies of endometriosis are contraceptive, great efforts should be targeted at researching novel products that reduce the disease expression without shuttering ovulation.
Publication
Santulli P, Borghese B, Chouzenoux S, Streuli I, Borderie D, de Ziegler D, Weill B, Chapron C, Batteux F
• 01/2013
OBJECTIVE: To determine the serum levels of interleukin (IL)-10 family ILs in women with ovarian endometriosis and investigate the correlation of these levels with disease activity. DESIGN: A case-control laboratory study. SETTING: Tertiary-care university hospital. PATIENT(S): Two hundred nineteen women, with (n = 112) and without (n = 107) endometriosis. INTERVENTION(S): Complete surgical excision with pathological analysis. MAIN OUTCOME MEASURE(S): Blood samples were obtained during surgical procedures. IL-10, -19, -20, and -22 were assayed by ELISA in sera, and the concentrations correlated with the extent and the severity of the disease. RESULT(S): IL-19 was detectable in 18.3% and IL-22 in 47.9% of sera samples from all 219 women studied. Serum IL-19 was lower in women with endometriosis (median, 292.7 pg/mL; range, 32.2-1,339.3) than in endometriosis-free women (median, 1,035.8 pg/mL; range, 32.2-2,000.0). In addition, serum IL-22 levels were decreased in women affected by endometriosis (median, 352.0 pg/mL; range, 31.2-1,392.2) as compared with endometriosis-free women (median, 709.2 pg/mL; range, 73.3-2,012.0). We found significant correlations between serum IL-22 concentrations and intensity of deep dyspareunia (r = -0.303) and noncyclic chronic pelvic pain (r = -0.212). IL-19 was correlated with the intensity of deep dyspareunia (r = -0.749). CONCLUSION(S): Serum IL-19 and IL-22 are decreased in women with ovarian endometrioma. IL-10 family ILs may be involved in the pathogenesis of endometriosis.
Publication
Vatier C, Kadiri S, Muscat A, Chapron C, Capeau J, Antoine B
• 12/2012
OBJECTIVE: Experimental endotoxaemia induces subcutaneous adipose tissue inflammation and systemic insulin resistance in lean subjects. Glyceroneogenesis, by limiting free fatty acids (FFA) release from adipocytes, controls FFA homoeostasis and systemic insulin sensitivity. The roles of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in metabolic deregulation are intrinsically different. We compared the effect of lipopolysaccharide (LPS) on the inflammation profiles of SAT and VAT explants from lean women, as well as on glyceroneogenesis, to test whether these two fat depots have intrinsically different responses to this metabolic endotoxin. DESIGN: Abdominal SAT and VAT explants from eight lean women were treated in vitro with LPS. Their inflammatory status was evaluated by cytokine gene expression and secretion; glyceroneogenesis was evaluated by cytosolic phosphoenolpyruvate carboxykinase activity and FFA vs glycerol release. RESULTS: In the basal state, the cytokine status and expression of macrophage markers were lower in SAT than VAT. In the presence of 100 ng ml(-1) LPS, SAT exhibited a strong inflammatory response (increased interleukin-6 and tumor necrosis factor-α expression) and increased release of FFA due to inhibition of glyceroneogenesis, whereas VAT was only mildly affected. The effects of LPS on both tissues were blocked by the nuclear factor-κB (NF-κB) inhibitor, parthenolide. A significant effect of LPS on VAT occurred only at 1 μg ml(-1) LPS. CONCLUSION: SAT explants from lean women are more sensitive to LPS-induced NF-κB activation than are VAT explants, leading to a depot-specific dysfunction of FFA storage. As SAT is the major player in FFA homoeostasis, this SAT dysfunction could be associated with visceral fat hypertrophy and systemic lipid disorders.
Publication
Streuli I, de Ziegler D, Gayet V, Santulli P, Bijaoui G, de Mouzon J, Chapron C
• 11/2012
STUDY QUESTION: Are anti-Müllerian hormone (AMH) levels lower in women with endometriosis, notably those with endometriomas (OMAs) and deep infiltrating lesions, compared with controls without endometriosis? SUMMARY ANSWER: Endometriosis and OMAs per se do not result in lower AMH levels. AMH levels are decreased in women with previous OMA surgery independently of the presence of current OMAs. WHAT IS KNOWN ALREADY: The impact of endometriosis and OMAs per se on the ovarian reserve is controversial. Most previous studies have been conducted in infertile women. The strength of our study lies in the following points: (i) the selection of women undergoing surgery and not only according to the presence of infertility, (ii) the classification of women with endometriosis and controls based on strict surgical and histological criteria. STUDY DESIGN, SIZE, DURATION: Cross-sectional study using data prospectively collected in all non-pregnant <42-year-old patients, who were surgically explored for a benign gynaecological condition at a university tertiary referral centre between 2004 and 2008. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. AMH levels were measured in serum samples drawn in the month preceding surgery, without regard to menstrual phase or hormonal therapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Operations were done on 1262 women between 2004 and 2008, of which 1133 signed the informed consent. Of the 566 women with a visual diagnosis of endometriosis, 411 had histologically proven endometriosis. Frozen serum samples for the AMH measurement were available in 313 of them. Out of the 554 women without visual endometriosis and without past endometriosis surgery, 413 had a frozen serum sample for the AMH measurement. Univariate analysis examined AMH levels according to baseline patient characteristics, the presence and type of endometriosis (superficial lesion, OMA, deep infiltrating lesion) and previous OMA surgery. Analysis of variance-covariance then examined the effects of co-variables on AMH levels. Finally, logistic regressions were conducted to examine the odds ratio (OR) of having AMH levels <1 ng/ml according to the same co-variables. MAIN RESULTS AND THE ROLE OF CHANCE: The difference in AMH levels between women with endometriosis and controls did not reach significance (3.6 ± 3.1 versus 4.1 ± 3.4 ng/ml, P = 0.06). Analysis of variance-covariance demonstrated that AMH levels significantly decreased with age (P < 0.001) and in women with prior OMA surgery irrespective of whether OMAs were present or not at the time of study (P < 0.05). Logistic regression revealed that two major factors were related to AMH levels <1 ng/ml: (i) age (compared with <29 years; 30-34 years OR = 3.1, 95% CI: 1.5-6.4, P = 0.01; 35-39 years OR = 7.0, 95% CI: 3.5-14.1, P = 0.001; ≥40 years OR = 20.8, 95% CI: 9.1-47.4, P = 0.001) and (ii) prior OMA surgery (OR = 3.0, 95% CI: 1.4-6.41, P = 0.01). LIMITATIONS, REASONS FOR CAUTION: The selection of our study population was based on a surgical diagnosis. Women with an asymptomatic form of endometriosis are therefore not included in our study. We cannot exclude that infertile women with OMAs associated with a diminished ovarian reserve, as assessed during their infertility work-up, were less likely to be referred for surgery and might therefore be underrepresented. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that OMAs per se do not diminish the ovarian reserve reflected by AMH levels but that alterations seen in women with endometriosis are a deleterious consequence of OMA surgery. These findings should be taken into account in the decision to operate OMAs in women with a desire for future pregnancy. STUDY FUNDING: none. Potential competing interests: none.
Publication
Carmona F, Chapron C, MartínezZamora MÁ, Santulli P, Rabanal A, MartínezFlorensa M, Lozano F, Balasch J
• 09/2012
Cytokines, and specifically interleukin 6 (IL-6) and interleukin 8 (IL-8), have been associated with the pathogenesis of endometriosis. We studied serum concentrations of IL-6 and IL-8 in patients with deep infiltrating endometriosis (DIE) or ovarian endometriomas (OE), but no other forms of associated endometriosis disease type. We carried out a case-control study including 19 patients with OE alone (OE group), 14 patients with DIE alone (DIE group) and 24 healthy patients without endometriosis (C group). Serum concentrations of IL-6 and IL-8 were measured in the three groups of patients. Serum levels of both IL-6 and IL-8 were significantly higher in the OE group. A high positive correlation was found between serum IL-6 and IL-8 levels in the OE group but not in the DIE and C groups. Serum IL-8 alone achieved the highest predictive value of the presence of OE (adjusted OR: 1.44; sensitivity: 78.2%; specificity: 76.2%). The combination of IL-6 and IL-8 levels did not significantly improve the discrimination between subjects with OE and those with DIE over that of IL-8. OE but not DIE are associated with increased serum levels of IL-6 and IL-8, and thus these may become useful tools for discriminating OE alone from DIE.
Publication
de Ziegler D, Streuli I, Gayet V, Frydman N, Bajouh O, Chapron C
• 08/2012
It has been two decades since pregnancies have been obtained through in vitro maturation (IVM) of germinal vesicle-stage oocytes retrieved from non-stimulated ovaries. This technique first offered in PCOS cannot be recommended today in this indication because the results do not match those of regular ART, and new GnRH antagonist and agonist-trigger protocols reliably prevent OHSS.
Publication
Santulli P, Borghese B, Chouzenoux S, Vaiman D, Borderie D, Streuli I, Goffinet F, de Ziegler D, Weill B, Batteux F, Chapron C
• 07/2012
BACKGROUND: Interleukin 33 (IL-33) is a cytokine involved in fibrotic disorders. We have analyzed IL-33 levels in the sera and peritoneal fluids of women with various forms of endometriosis and investigated the correlation with disease activity. METHODS: We conducted a prospective laboratory study in a tertiary-care university hospital between January 2005 and December 2010. Five hundred and ten women with histologically proven endometriosis and 132 endometriosis-free controls were enrolled in this study. Complete surgical exploration of the abdominopelvic cavity was performed in each patient. Blood samples and peritoneal fluids were obtained before and during surgical procedures, respectively. IL-33 was measured by an enzyme-linked immunosorbent assay in sera and peritoneal fluids, and the concentrations correlated with the extent and the severity of endometriotic lesions. RESULTS: IL-33 was detectable in 23.1% of serum samples from all 642 women studied and 75.0% of peritoneal fluid samples studied (44 women with endometriosis and 36 controls). Serum IL-33 was higher in deeply infiltrating endometriosis (DIE) (median, 104.9 pg/ml; range, 8.0-104.9) than in endometriosis-free women (median, 61.3 pg/ml; range, 7.5-526.0; P = 0.022) or in women affected by superficial endometriosis (median, 36.8 pg/ml; range, 7.5-179.0; P < 0.001). Peritoneal IL-33 was higher in DIE than in endometriosis-free women (median, 642.0 pg/ml; range, 25.9-3350.6 versus median, 194.2 pg/ml; range, 12.7-1818.2, respectively; P = 0.003). We found positive correlations between serum IL-33 concentration and intensity of dysmenorrhea (r = 0.174; P = 0.028) and gastrointestinal symptoms (r = 0.199; P = 0.027), total number of DIE lesions (r = 0.224; P = 0.016) and the worst DIE lesion (r = 0.299; P < 0.001). CONCLUSIONS: In spite of the number of samples with undetectable levels, serum IL-33 is abnormally elevated in women with endometriosis and principally in DIE. Elevated serum IL-33 is correlated with the intensity of preoperative painful symptoms, and with the extent and severity of the DIE. IL-33 may be considered as a novel cytokine involved in the pathogenesis of DIE.
