Publication
Petraglia F, Arcuri F, de Ziegler D, Chapron C
• 07/2012
Endometriosis is a chronic inflammatory disease affecting women's health. Pain and infertility are the major symptoms caused by a hormonal/immunological dysfunction, which causes an endometrial impairment. The same pathogenetic mechanisms are also associated with preterm birth: hormones, cytokines, neurohormones, and growth factors interact in modulating extracellular matrix and prostaglandin secretion, thus activating the inflammatory process in placental membranes and myometrium. An overlap of molecules and mechanisms may explain the evidence that preterm birth is a common outcome in pregnant patients with endometriosis.
Publication
Borghese B, Santulli P, Héquet D, Pierre G, de Ziegler D, Vaiman D, Chapron C
• 05/2012
Endometrioma is a common ovarian cyst associated with pain and infertility, but its pathogenesis remains enigmatic. Demonstration of the subtelomeric location of hypermethylation in endometrioma has been reported by genome-wide profiling of methylated promoters. Recently, rs113593938, a polymorphism in the DNA methyltransferase 3-like (DNMT3L) gene has been associated with subtelomeric hypomethylation. We investigated the association between endometrioma and rs113593938, rs8129776, rs7354779, and rs2276248, which were chosen for thoroughly covering the locus of interest. We enrolled 127 patients with histologically proved endometrioma and no associated deep endometriotic lesions and 317 healthy subjects for a case-control genetic association study. Genotyping was performed after PCR amplification of the region encompassing the polymorphisms, restriction enzyme digestion, and detection of fragments on an agarose gel. Differences in genotype and allele distributions between cases and controls were tested for each polymorphism separately using the χ(2) test. The rs8129776 was significantly associated with endometrioma (P = 0.003). Haplotype analysis showed a higher risk for the patients carrying the ACCC+T haplotypes for rs8129776, rs7354779, rs113593938, and rs2276248 (odds ratio, 7.15; 95% CI, 2.63 to 19.44). We report, for the first time to our knowledge, the association of DNMT3L genetic variants and endometrioma; DNMT3L expression itself was not modified. Our study constitutes a first milestone toward a plausible role of DNMT3L in the establishment of specific DNA methylation patterns in endometrioma.
Publication
Leconte M, Borghese B, Chapron C, Dousset B
• 04/2012
Endometriosis affects 6 to 10 % of all women of childbearing age. Intestinal involvement is defined by muscularis infiltration and has been estimated to occur in 8 % to 12 % of women with endometriosis. The most common sites are rectum, sigmoid and ileocaecal junction. In most cases, intestinal endometriosis is associated with deep infiltrating endometriosis, multifocal and aggressive form of endometriosis, responsible for refractory pelvic pain and infertility. The symptoms are nonspecific but are characterized by cyclic exacerbation of pain. The preoperative work-up includes a rectal endoscopic ultrasonography, a transvaginal ultrasonography, a pelvic magnetic resonance imaging and a multidetector CT scan. There is currently no cure other than surgical removal of lesions. Medical treatments are based on a hormone used to block ovarian function.
Publication
Santulli P, Marcellin L, Noël JC, Borghese B, Fayt I, Vaiman D, Chapron C, Méhats C
• 04/2012
OBJECTIVE: To investigate key genes expression of the sphingosine-1-phosphate pathway in endometriotic tissues. DESIGN: A case-control laboratory study. SETTING: Tertiary care university hospital. PATIENT(S): A total of 31 women, with (n = 16) and without (n = 15) endometriosis took part in the study. INTERVENTION(S): After surgical excision with pathological analysis, endometrial specimens were obtained from women affected or not by endometriosis. MAIN OUTCOME MEASURE(S): SPHK1-2, SGPP1-2, SGPL1, SPHKAP, and S1PR1-5 messenger RNA expression by quantitative real-time polymerase chain reaction (PCR) in the endometrium of 15 disease-free women, 16 eutopic and 16 ectopic endometrium of endometriosis-affected women. The S1PR1 and S1PR2 expression were further investigated by immunohistochemistry. RESULT(S): The SGPP2 expression was decreased in eutopic and ectopic endometrium of endometriosis-affected women (1.7- and 16.7-fold, respectively). The SGPP1, weakly expressed in healthy endometrium, is up-regulated in endometriosis-affected women (11.9- and 64.7-fold, respectively), but its expression remains low. The SGPL1 expression was decreased in ectopic endometrium (3.3-fold) and SPHKAP expression was increased in ectopic endometrium (112.6-fold) compared with endometrium of disease-free women. In endometriosis-affected women, S1PR3 expression was decreased in eutopic and ectopic endometrium (2.1- and 6.3-fold, respectively); S1PR2 and S1PR1 expression was increased in eutopic (2.5-fold) and ectopic endometrium (2.6-fold). These increases were confirmed at the protein levels by immunohistochemistry. CONCLUSION(S): Expression of the enzymes implicated in the regulation of the sphingosine-1-phosphate level balance and of its receptors is overall heavily deregulated in endometriotic lesions in favor of a decreased sphingosine-1-phosphate catabolism. Our results plead for a role of the sphingosine pathway in establishing and survival of endometriotic lesions.
Publication
Streuli I, de Ziegler D, Borghese B, Santulli P, Batteux F, Chapron C
• 03/2012
Introduction: Endometriosis, histologically defined as the presence of endometrium-like tissue - glands and stroma - that develops outside of the uterine cavity, is still an enigmatic disease responsible for pelvic pain and infertility. The current treatments of endometriosis are surgery and hormonal therapies that act by suppressing ovulation and/or directly on steroid receptors located in endometriotic lesions. Areas covered: New hormonal and non-hormonal therapies are being developed for the treatment of endometriosis-related pain. The authors review the state of advancement and the results of novel treatments studied in registered trials ( www.ClinicalTrials.gov ). Cellular signaling pathways activated in endometriotic cells, which constitute potential targets for future treatments, are also described. Expert opinion: Therapeutic research efforts should focus on identifying and testing substances capable of acting locally on the lesions themselves, without interfering with ovulation, in order to be efficacious on both pain symptoms and infertility.
Publication
Chapron C, Santulli P, de Ziegler D, Noel JC, Anaf V, Streuli I, Foulot H, Souza C, Borghese B
• 03/2012
BACKGROUND: The objective of this study was to evaluate the significance of severe preoperative pain for patients presenting with ovarian endometrioma (OMA). METHODS: Three hundred consecutive patients with histologically proven OMA were enrolled at a single university tertiary referral centre between January 2004 and May 2010. Complete surgical excision of all recognizable endometriotic lesions was performed for each patient. Pain intensity was assessed with a 10-cm visual analogue scale (VAS). Pain was considered as severe when VAS was ≥ 7. Prospective preoperative assessment of type and severity of pain symptoms (VAS) was compared with the peroperative findings (surgical removal and histological analysis) of endometriomas and associated deeply infiltrating endometriosis. Correlations were sought with univariate analysis and a multiple regression logistic model. RESULTS: After multiple logistic regression analysis, uterosacral ligaments involvement was related with a high severity of chronic pelvic pain [odds ratios (OR) = 2.1; 95% confidence interval (CI): 1.1-4.3] and deep dyspareunia (OR = 2.0; 95% CI: 1.1-3.5); vaginal involvement was related with a higher intensity of lower urinary symptoms (OR = 13.4; 95% CI: 3.2-55.8); intestinal involvement was related with an increased severity of dysmenorrhoea (OR = 5.2; 95% CI: 2.7-10.3) and gastro-intestinal symptoms (OR = 7.1; 95% CI: 3.3-15.3). CONCLUSIONS: In case of OMA, severe pelvic pain is significantly associated with deeply infiltrating lesions. In this situation, the practitioner should perform an appropriate preoperative imaging work-up in order to evaluate the existence of associated deep nodules and inform the patient in order to plan the surgical intervention strategy.
Publication
Lafay Pillet MC, Schneider A, Borghese B, Santulli P, Souza C, Streuli I, de Ziegler D, Chapron C
• 01/2012
BACKGROUND: An inverse association between BMI and endometriosis has been reported but remains controversial. We decided to evaluate the association between BMI and the different types of endometriosis, classified as superficial endometriosis (SUP), deep infiltrating endometriosis (DIE) and ovarian endometrioma (OMA). METHODS: From a prospective database of patients who underwent gynecological surgery between February 2005 and October 2008, we compared 238 patients with a histological diagnosis of endometriosis to 238 age- and smoking-status-matched controls using a prospective preoperative questionnaire and surgical data. Numerical variables means were compared for matched pairs, and non-parametric variables using Wilcoxon test. The Odds ratios for all types of endometriosis adjusted for confounding variables were computed according to predefined BMI groups [1(<18.5), 2 (≥18.5 and <22), 3(≥22 and <25), 4(≥25)], taking Group 3 as the reference population. RESULTS: BMI was significantly lower for all 238 patients (21.70 ± 3.7 versus 23.29 ± 4.1, P < 0.001), for 101 OMA patients (21.88 ± 3.8 versus 22.99 ± 4, P < 0.038), and for 97 DIE patients (21.35 ± 3.4 versus 23.35 ± 3.8, P < 0.001) compared with their own controls, but not for the 40 SUP patients. Patients in Group 1 had adjusted odds ratios as high as 3.3 [95% confidence interval (CI): 1.6-6.8] for DIE and 2.7 (95% CI: 1.1-6.8) for OMA; in Group 2, the adjusted oddd ratios were 2.6 (95% CI: 1.3-5.5) for DIE and 2.9 (95% CI: 1.5-5.4) for OMA. CONCLUSIONS: Endometriotic patients have lower BMI than age- and smoking-status-matched controls, independent of confounding variables. Patients with the lowest BMI (<18.5) are at a high risk of DIE.
Publication
de Ziegler D, Streuli I, Meldrum DR, Chapron C
• 11/2011
Recently, three meta-analyses have concluded that cotreatment with GH improves assisted reproduction outcome in poor controlled ovarian stimulation responders. Although generally GH supplements did not increase controlled ovarian stimulation response or number of oocytes, the supplements improved pregnancy and live-birth rates-thus speaking for an effect on oocyte quality.
Publication
Chapron C, Borghese B, Streuli I, de Ziegler D
• 10/2011
Endometriosis, a disease of young females that is possibly a devastating ailment requiring surgery, appears to be associated with certain features encountered in adolescence. First among these symptoms is the history of severe and lasting dysmenorrhea at the time of adolescence and the need to use oral contraceptives (OCs) for alleviating dysmenorrhea that failed to respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Further awareness about existing associations between certain symptoms experienced at adolescence and the later development of endometriosis is important. Indeed, the possibility of diagnosing endometriosis earlier when suggested by clinical history could lead to less extensive surgery and thus, less damage. Experimental verification of this insight, however, is needed before the concept that early diagnosis means lesser destructive surgery can be ascertained.
Publication
Leconte M, Nicco C, Ngô C, Chéreau C, Chouzenoux S, Marut W, Guibourdenche J, Arkwright S, Weill B, Chapron C, Dousset B, Batteux F
• 08/2011
Deep infiltrating endometriosis (DIE) is a particular clinical and histological entity of endometriosis responsible for chronic pelvic pain and infertility. Here we characterize the proliferative phenotype of DIE cells, to explore the cellular and molecular mechanisms that could explain their aggressive potential. In addition, the inhibition of mTOR/AKT pathway was tested, as a potential treatment of DIE. Included were 22 patients with DIE and 12 control patients without endometriosis. Epithelial and stromal cells were extracted from biopsies of eutopic endometrium and deep infiltrating endometriotic nodules from patients with DIE. Cell proliferation was determined by thymidine incorporation. Oxidative stress was assayed by spectrofluorometry. The ERK and mTOR/AKT pathways were analyzed in vitro by Western blot and for AKT in vivo in a mouse model of DIE. The proliferation rate of eutopic endometrial cells and of deep infiltrating endometriotic cells from DIE patients was higher than that of endometrial cells from controls. The hyperproliferative phenotype of endometriotic cells was associated with an increase in endogenous oxidative stress, and with activation of the ERK and mTOR/AKT pathways. mTOR/AKT inhibition by temsirolimus decreased endometriotic cell proliferation both in vitro and in vivo in a mouse model of DIE. Blocking the mTOR/AKT pathway offers new prospects for the treatment of DIE.
