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Urologe A. 2007 Jan;46(1):71-8; quiz 79.

[Endometriosis of the ureter and urinary bladder]

[Article in German]

Zugor V, Krot D, Rösch WH, Schrott KM, Schott GE.

Urologische Klinik mit Poliklinik, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Krankenhausstrasse 12, Erlangen, Deutschland. vahudin.zugor@uro.imed.uni-erlangen.de

Endometriosis is a benign growth of ectopic endometrial mucous membrane which has maintained the histological characteristics and biological reactions of uterine mucous membrane. In only 1-2% of cases does it occur in the urinary system, most commonly in the urinary bladder. Such an endometriosis is often diagnosed very late due both to its commonly asymptomatic course and its rarity. Individual therapy is dependent on the age of the patient, the wish for children and the extent of the growth. For endometriosis covering a large area, surgery is recommended. Methods of choice are laparoscopic bladder resection for the urinary bladder, ureterocystoneostomy using the Psoas hitch for the distal ureter, end to end anastomosis or endoscopic incision for short, proximal cases, and for extended areas, ileum cross-bridge attachment or kidney mobilization using nephropexy.

Hum Reprod. 2007 Apr;22(4):1142-8. Epub 2006 Dec 20.

Deep dyspareunia and sex life after laparoscopic excision of endometriosis.

Ferrero S, Abbamonte LH, Giordano M, Ragni N, Remorgida V.

Department of Obstetrics and Gynaecology, San Martino Hospital, University of Genoa, Genoa, Italy. simone.ferrero@fastwebnet.it

BACKGROUND: Among subjects with endometriosis and deep dyspareunia (DD), those with endometriosis of the uterosacral ligament (USLE) have the most severe impairment of sexual function. This study examines the effect of laparoscopic excision of endometriosis on DD and quality of sex life. METHODS: This observational cohort prospective study included 68 women with endometriosis suffering DD (intensity of pain >or= 6 on a 10-cm visual analogue scale). Patients underwent laparoscopic full excision of endometriosis. Following surgery, they were asked to use nonhormonal contraception devices. Before surgery, at 6- and at 12-month follow-up, patients answered a self-administered questionnaire based on the Sexual Satisfaction Subscale of the Derogatis Sexual Functioning Inventory. RESULTS: At 6- and 12-month follow-up, women with and without USLE had significant improvement in DD. Subjects with USLE reported increased variety in sex life, increased frequency of intercourse, more satisfying orgasms with sex, relaxing more easily during sex and being more relaxed and fulfilled after sex. Similar improvements were observed among women without USLE; however, for some variables statistical significance was not reached. CONCLUSIONS: Surgical excision of endometriosis improves not only DD but also the quality of sex life.

AJR Am J Roentgenol. 2007 Jan;188(1):176-81.

Long-term results of uterine artery embolization for symptomatic adenomyosis.

Kim MD, Kim S, Kim NK, Lee MH, Ahn EH, Kim HJ, Cho JH, Cha SH.

Department of Diagnostic Radiology, Bundang CHA General Hospital, Pochon CHA University, 351 Yatap-dong, Bundang-gu, Sungnam-si, Kyonggi-do, 463-712, Republic of Korea. mdkim@cha.ac.kr

OBJECTIVE: Controversy exists regarding the effectiveness of uterine artery embolization (UAE) in the management of symptomatic adenomyosis. The aim our study was to determine the long-term clinical efficacy of UAE in the management of symptomatic adenomyosis without fibroids. MATERIALS AND METHODS: The cases of all patients who underwent UAE for adenomyosis without fibroids between 1998 and 2000 were analyzed. This study was a retrospective review of a prospectively collected database. Of the 66 patients, 54 patients with a follow-up period of 3 years or longer were enrolled in the study. Twelve patients were lost to follow-up. The patients’ ages ranged from 29 to 49 years (mean, 40.2 years). The mean follow-up period was 4.9 years (range, 3.5-5.8 years). The primary embolic agent was polyvinyl alcohol particles (250-710 microm). All patients underwent MRI before UAE. Long-term follow-up MRI was performed on 29 patients; 22 of these patients had undergone short-term (3.5 months) follow-up MRI. Uterine volume was calculated with MR images. Symptom status in terms of menorrhagia and dysmenorrhea was scored on a scale of 0-10, 0 being no symptoms and 10 being the baseline, or initial symptoms. RESULTS: Thirty-one (57.4%) of the 54 women who underwent follow-up had long-term success. Four had immediate treatment failure, and 19 had relapses. Changes in mean menorrhagia and dysmenorrhea scores at long-term follow-up were -5.3 and -5.1, respectively (p < 0.001), representing significant relief of symptoms. The time between UAE and recurrence of symptoms ranged from 4 to 48 months (mean, 17.3 months). Five patients underwent hysterectomy because of symptom recurrence. Mean reduction in volume of the uterus was 26.3% at short-term follow-up and 27.4% at long-term follow-up. CONCLUSION: We found that UAE is effective in the management of symptomatic adenomyosis and has an acceptable long-term success rate. UAE should be considered a primary treatment method for patients with symptomatic adenomyosis. However, all patients should be given an explanation of the possibility of treatment failure, recurrence, and the need for hysterectomy.

Mol Hum Reprod. 2007 Feb;13(2):135-40. Epub 2006 Dec 18.

Interleukin-10 gene promoter polymorphisms and their protein production in peritoneal fluid in patients with endometriosis.

Zhang X, Hei P, Deng L, Lin J.

Department of Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang, PR China.

Although associations of interleukin-10 (IL-10) gene promoter polymorphisms and their protein production with endometriosis risk have been reported, the correlations remain controversial. The objective of this study was to determine IL-10 gene promoter polymorphisms at -1082, -819 and -592 sites and their protein production in peritoneal fluid (PF) in patients with and without endometriosis. IL-10 gene promoter polymorphisms at -1082 site were detected by amplification refractory mutation system (ARMS)-PCR and that at -819 and -592 sites was genotyped by restriction fragment length polymorphism (RFLP)-PCR. Protein levels of IL-10 in PF were measured by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in the genotype and allele frequencies of IL-10 gene promoter polymorphisms at position -1082 between the endometriosis and the control groups. However, the frequency of -819 or -592 C alleles was significantly increased in patients with endometriosis compared with controls. The protein levels of IL-10 in PF were statistically higher in the endometriosis group than in the control group. Moreover, the polymorphisms at -1082, -819 and -592 sites were associated with protein levels of IL-10 in PF in the endometriosis group while in the control group only the polymorphisms at position -1082 correlated with protein levels. Increased frequency of -819 or -592 C allele and increased protein production of IL-10 in PF in patients with endometriosis compared with controls and correlations of polymorphisms at -819 and -592 sites with protein levels of IL-10 in PF in patients with endometriosis may suggest that polymorphisms at -819 and -592 sites and their protein production are associated with endometriosis risk.

Fertil Steril. 2007 Mar;87(3):697.e1-4. Epub 2006 Dec 14.

Spontaneous viable pregnancies in cervical and rectal endometriosis: a report of two cases.

Ganesh AL, Chakravarty B.

School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, Kolkata, India.

OBJECTIVE: To report two cases of advanced pelvic endometriosis, both with deep rectal involvement and one with extensive cervical involvement appearing like a carcinoma, where both patients achieved spontaneous pregnancy and delivered viable babies. DESIGN: Case report. SETTING: Institute of Reproductive Medicine. PATIENT(S): Two nulliparous patients, one with extensive cervical and rectal and other with deep rectal endometriosis and primary infertility. INTERVENTION(S): Medical management. MAIN OUTCOME MEASURE(S): Description and treatment of two patients with advanced pelvic endometriosis and pregnancy. RESULT(S): Delivery of viable babies in both cases. CONCLUSION: Prolonged medical treatment may have helped to arrest the progression of the disease by restoring anatomic proximity leading to spontaneous pregnancy in both cases.

Diagn Cytopathol. 2007 Jan;35(1):12-7.

Weeding atypical glandular cell look-alikes from the true atypical lesions in liquid-based Pap tests: a review.

Wood MD, Horst JA, Bibbo M.

Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. moira.wood@mail.tju.edu

The purpose of this review is to identify features that separate atypical glandular cells (AGC) associated with glandular neoplasia from its mimickers, both benign and neoplastic. We reviewed cases of AGC diagnosed on liquid-based Pap tests (LBP) for which corresponding histological follow-up was available. A review of the literature for similar studies in LBP tests was also conducted. We find that certain benign mimics can be reliably separated from AGC, but recommend caution in attempting to increase specificity at the risk of losing sensitivity. Although accounting for only a small percentage of diagnoses AGC require a thorough clinical evaluation, including colposcopy. Most cases are ultimately found to be benign. When evaluating smears suspicious for AGC, it is important to examine the subtle features which make truly atypical cells discernible from their numerous benign mimickers.

BJOG. 2007 Feb;114(2):165-9. Epub 2006 Dec 4.

Comment in:

BJOG. 2007 Jul;114(7):907; author reply 908.

Adenomyosis and risk of preterm delivery.

Juang CM, Chou P, Yen MS, Twu NF, Horng HC, Hsu WL.

Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, and Department of Epidemiology, Institute of Public Health, National Yang-Ming University, Taipei, Taiwan. cmjuang@yahoo.com.tw

OBJECTIVE: To evaluate the risk of preterm delivery in patients with adenomyosis. DESIGN: A 1:2 nested case-control study. SETTING: Tertiary-care institution. POPULATION: A base cohort population of 2138 pregnant women who attended routine prenatal check-up between July 1999 and June 2005. METHODS: From this base cohort population, gravid women with singleton pregnancy who delivered prior to the completion of 37 weeks of gestation were identified and formed the study group. Singleton gravid women who had term delivery and who matched with age, body mass index, smoking, and status of previous preterm delivery were recruited concurrently and served as control group. Preterm delivery cases were further divided into spontaneous preterm delivery and preterm premature rupture of membranes (PPROM) cases. MAIN OUTCOME MEASURES: Risk analysis of preterm delivery between gravid women with and without adenomyosis. RESULTS: One-hundred and four preterm delivery case subjects and 208 control subjects were assessed. Overall, gravid women with adenomyosis were associated with significantly increased risk of preterm delivery (adjusted odds ratio 1.96, 95% CI 1.23-4.47, P=0.022). For subgroup analysis, gravid women with adenomyosis had an adjusted 1.84-fold risk of spontaneous preterm delivery (95% CI 1.32-4.31, P=0.012) and an adjusted 1.98-fold risk of PPROM (95% CI 1.39-3.15, P=0.017). CONCLUSIONS: Gravid women with adenomyosis were associated with increased risk of both spontaneous preterm delivery and PPROM. A common pathophysiological pathway may exist in these two disorders. Further in-depth biochemical and molecular studies are necessary to explore this phenomenon.

Gynecol Obstet Invest. 2007;63(4):205-8. Epub 2006 Dec 7.

Perioperative predictors of successful hysteroscopic endometrial ablation.

Gemer O, Kruchkovich J, Huerta M, Kapustian V, Kroll D, Anteby E.

Department of Obstetrics and Gynecology Barzilai Medical Center, Ashkelon, Israel. gemer@barzi.health.gov.il

OBJECTIVE: To determine which perioperative factors influence the success of hysteroscopic endometrial ablation in patients with menorrhagia. STUDY DESIGN: A longitudinal study of 128 women who underwent hysteroscopic endometrial ablation or resection. Clinical data included age, uterine size, the presence of intramural or submucosal myomas and polyps, and length of follow-up from initial hysteroscopic ablation to re-ablation or hysterectomy (‘failure’). Kaplan-Meier survival analysis, log-rank tests and Cox proportional hazard regression were used to evaluate the equality of survival distributions and to model the overall effects of the various predictor variables on surgical outcomes. RESULTS: Patients were followed for a median time of 44 months. Thirteen women (10.2%) underwent a second operative procedure. Multivariate analysis identified submucosal myoma as a statistically significant positive predictor of the risk of failure [hazard ratio (HR) 5.22, 95% confidence interval (CI) = 1.63, 16.73)]. Older age was associated with a marginally lower risk of subsequent surgery (HR 0.90 per additional year of age, 95% CI = 0.81, 1.00). CONCLUSIONS: The presence of submucosal myoma increases the risk of subsequent surgery in patients undergoing endometrial ablation.

Hum Reprod. 2007 Mar;22(3):717-28. Epub 2006 Dec 11.

Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13-15.

Zondervan KT, Treloar SA, Lin J, Weeks DE, Nyholt DR, Mangion J, MacKay IJ, Cardon LR, Martin NG, Kennedy SH, Montgomery GW.

Wellcome Trust Centre for Human Genetics, University of Oxford, UK. krinaz@well.ox.ac.uk

BACKGROUND: Endometriosis is a common disease with a heritable component. The collaborative International Endogene Study consists of two data sets (Oxford and Australia) comprising 1176 families with multiple affected. The aim was to investigate whether the apparent concentration of cases in a proportion of families could be explained by one or more rare variants with (near-)Mendelian autosomal inheritance. METHODS AND RESULTS: Linkage analyses (aimed at finding chromosomal regions harbouring disease-predisposing genes) were conducted in families with three or more affected (Oxford: n = 52; Australia: n = 196). In the Oxford data set, a non-parametric linkage score (Kong & Cox (K&C) Log of ODds (LOD)) of 3.52 was observed on chromosome 7p (genome-wide significance P = 0.011). A parametric MOD score (equal to maximum LOD maximized over 357 possible inheritance models) of 3.89 was found at 65.72 cM (D7S510) for a dominant model with reduced penetrance. After including the Australian data set, the non-parametric K&C LOD of the combined data set was 1.46 at 57.3 cM; the parametric analysis found an MOD score of 3.30 at D7S484 (empirical significance: P = 0.035) for a recessive model with high penetrance. Critical recombinant analysis narrowed the probable region of linkage down to overlapping 6.4 Mb and 11 Mb intervals containing 48 and 96 genes, respectively. CONCLUSIONS: This is the first report to suggest that there may be one or more high-penetrance susceptibility loci for endometriosis with (near-)Mendelian inheritance.

Am J Reprod Immunol. 2007 Jan;57(1):49-54.

Expression of glycodelin and cyclooxygenase-2 in human endometrial tissue following three-dimensional culture.

Esfandiari N, Ai J, Nazemian Z, Javed MH, Gotlieb L, Casper RF.

Toronto Centre for Advanced Reproductive Technology, and Division of Reproductive Sciences, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada. nesfand@excite.com

PROBLEM: Our previous study showed that in vitro culture of human endometrial tissue in a three-dimensional (3D) fibrin matrix could mimic the early stages of endometriosis with invasion, gland and stroma formation and sprouting of new vessels. The objective of the present study was to evaluate the expression of glycodelin (Gd) and cyclooxygenase-2 (COX-2), two angiogenic factors, to further validate the 3D culture model of endometriosis. METHOD OF STUDY: Human endometrial fragments were obtained from endometrial biopsies and placed in a 3D fibrin matrix culture. Immunohistochemistry with specific antibodies to Gd and COX-2 was used to examine endometrial epithelium and blood vessels, and 4, 6-diamidino-2-phenylindole staining was used for nuclear identification. RESULTS: Three-dimensional culture of human endometrial tissue in the fibrin matrix resulted in the proliferation of endometrial stromal cells, glandular epithelium and angiogenesis. Gd positive glandular epithelium was seen in 85% of wells with developing endometrial glands and COX-2 positive new vessels were seen in 80% of wells with angiogenesis-like structures after 4 weeks of culture. CONCLUSION: Our findings confirm that angiogenesis occurs following the culture of endometrial tissue in the 3D fibrin matrix, and suggests that Gd and COX-2 might play important roles in promoting neovascularization and cell proliferation in the establishment of endometriosis.

Abdom Imaging. 2007 Jul-Aug;32(4):441-50.

Bowel endometriosis: CT-enteroclysis.

Biscaldi E, Ferrero S, Remorgida V, Rollandi GA.

Department of Radiology, Galliera Hospital, Via Mura delle Capuccine 14, 16128, Genoa, Italy. ennio.biscaldi@fastwebnet.it

Although several radiological techniques have been used for the diagnosis of bowel endometriosis, no gold standard is currently established. We used multislice computerized tomography (CT) combined with the distention of the colon by rectal enteroclysis (MSCTe) for the diagnosis of bowel endometriosis. Following bowel preparation, pharmacological hypotonicity, retrograde colonic distention by water enteroclysis, and intravenous injection of iodinated contrast medium, a single volumetric acquisition of the abdomen is performed. MSCTe findings suggestive of bowel endometriosis are the presence of solid nodules with positive enhancement, contiguous or penetrating the colonic wall. When endometriotic lesions are detected, the degree of infiltration of the intestinal wall can be estimated; however, the depth infiltrated by nodules reaching the submucosa may be underestimated. MSCTe is well tolerated by the patients. The strength of MSCT consists in the high spatial resolution; volumetric data acquired by using thin slices provide isotropic voxels and multiplanar reconstructions have a quality comparable with that of the original axial scans. The potential of MSCTe for the diagnosis of bowel endometriosis relies on the fact that the serosal, muscular, and mucosal layers of the bowel wall can be evaluated.

Fertil Steril. 2007 Feb;87(2):373-80. Epub 2006 Dec 4.

Intraobserver and interobserver reliability of videotaped laparoscopy evaluations for endometriosis and adhesions.

Weijenborg PT, ter Kuile MM, Jansen FW.

Department of Gynecology, Leiden University Medical Center, Leiden, The Netherlands. p.t.m.weijenborg@lumc.nl <p.t.m.weijenborg@lumc.nl>

OBJECTIVE: To determine the intra- and interobserver reliability of evaluations during videotaped laparoscopy, with real-time laparoscopy as the “gold standard.” DESIGN: Prospective evaluation. SETTING: University hospital. PATIENT(S): Women who underwent laparoscopy for chronic pelvic pain, sterilization, or infertility workup. INTERVENTION(S): Real-time laparoscopies were videotaped and scored then later reassessed. MAIN OUTCOME MEASURE(S): Intra- and interobserver levels of agreement between evaluations for endometriosis and adhesions. RESULT(S): With the use of reassessments on 90 (videotaped) laparoscopies, the intra- and interobserver levels of agreement between the scorings for endometriosis were found to be substantial, except for ovarian implantations. A high agreement was found in the staging of endometriotic disease. The intra- and interobserver levels of agreement for scoring adhesions were only fair to moderate, and a substantial number of differences between measurements in adhesion total scores was found. No systematic difference between the number of disagreements was observed in either setting. CONCLUSION(S): Although special attention has to be given to the assessments of ovarian lesions, the evaluations of videotaped laparoscopies for endometriosis were reliable and justified the use of recorded findings. Because evaluations of adhesions during videotaped laparoscopy are not reliable, in some cases a second laparoscopy may need to be performed.

Fertil Steril. 2007 Mar;87(3):651-6. Epub 2006 Nov 29.

Endometriosis may be generated by mimicking the ontogenetic development of the female genital tract.

Gaetje R, Holtrich U, Engels K, Kissler S, Rody A, Karn T, Kaufmann M.

Department of Obstetrics and Gynecology, Johann Wolfgang Goethe-University, Frankfurt, Germany. gaetje@em.uni-frankfurt.de <gaetje@em.uni-frankfurt.de>

OBJECTIVE: To compare the expression of genes playing a decisive role during the embryonic development of the female genital tract (WNT4, WNT5A, WNT7A, PAX8) in the peritoneum of patients with endometriosis and control patients. DESIGN: Experimental study using real-time polymerase chain reaction and in situ hybridization. SETTING: University-based laboratory. PATIENT(S): Patients with and without endometriosis undergoing surgery for benign indications. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Percentage of samples positive for gene expression by using real-time polymerase chain reaction, as well as relative expression values compared with housekeeping genes. Confirmation of results by in situ hybridization. RESULT(S): Expression of WNT7A and PAX8 was found in the normal peritoneum in approximately half of the patients with endometriosis in contrast to the controls. In patients with endometriosis WNT7A and PAX8 in histologically normal peritoneum (with no evidence of endometriosis, endosalpingiosis, or other changes) were confirmed by in situ hybridization. CONCLUSION(S): The expression of these genes in the normal peritoneum suggests that endometriosis can arise through metaplasia and can in the process make use of the developmental steps involved in the embryonic development of the female genital tract.

Curr Opin Gastroenterol. 2007 Jan;23(1):67-73.

Recent developments in the role of endoscopic ultrasonography in diseases of the colon and rectum.

Bhutani MS.

Center for Endoscopic Ultrasound, University of Texas Medical Branch, Galveston, Texas 77555, USA. msbhutan@utmb.edu

PURPOSE OF REVIEW: Endoscopic ultrasound has evolved as a useful technique for imaging and intervention in a variety of gastrointestinal and extraintestinal diseases including diseases of the colon and rectum. This paper will review recent developments in endoscopic ultrasound for colorectal diseases. RECENT FINDINGS: Recent studies have shown significant clinical impact of endoscopic ultrasound in rectal cancer staging. Iliac lymph node evaluation by endoscopic ultrasound-guided fine needle aspiration may further expand the role of endoscopic ultrasound in rectal cancer. Three-dimensional endoscopic ultrasound may help decrease some of the errors of staging with two-dimensional endoscopic ultrasound and may further improve staging accuracy. Recent studies have confirmed continued problems with re-staging rectal cancer after chemoradiation. Endoscopic ultrasound-fine needle aspiration can be helpful in detecting local recurrence of rectal cancer and has been shown to be useful in evaluation of subepithelial masses of the colon and rectum and evaluation of rectosigmoid endometriosis. SUMMARY: Endoscopic ultrasound continues to be useful for a variety of conditions of the colon and rectum with recent studies confirming its clinical impact as well as expanding its role into newer indications. Assessment for residual cancer after chemoradiation is still problematic and hopefully technological developments in ultrasound in the future may help in improving the accuracy of endoscopic ultrasound in this situation.

Fertil Steril. 2007 Mar;87(3):485-9. Epub 2006 Nov 27.

Clinical evaluation of endometriosis and differential response to surgical therapy with and without application of Oxiplex/AP* adhesion barrier gel.

diZerega GS, Coad J, Donnez J.

Livingston Reproductive Biology Laboratories, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA. dizerega@usc.edu

OBJECTIVE: To correlate parameters of endometriosis obtained during routine clinical evaluation with the subsequent formation of adhesions following surgical treatment by laparoscopy. DESIGN: Randomized, controlled, double-blind, clinical trial. SETTING: Tertiary referral centers for the treatment of endometriosis. PATIENT(S): Thirty-seven patients (65 with adnexa) with stage I-III endometriosis; endometrioma-only patients were excluded. INTERVENTION: Laparoscopic surgical treatment of endometriosis, followed by randomization to Oxiplex/AP (FzioMed, Inc., San Luis Obispo, California) gel treatment (treated group) of adnexa, or surgery alone (control group); follow-up laparoscopy 6-10 weeks later. MAIN OUTCOME MEASURE(S): Adnexal Americn Fertility Society score, correlated with color and location of endometriosis, as well as stage of disease determined by masked review of videotapes. RESULT(S): Control patients with at least 50% red lesions had a greater increase in ipsilateral adnexal adhesion scores than patients with mostly black or white and/or clear lesions. Treated patients with red lesions had a greater decrease in adnexal adhesion scores than control patients. There was a correlation between baseline endometriosis stage and postoperative adhesion formation in control patients, but not treated patients. CONCLUSION(S): Patients with red endometriotic lesions had greater increases in their adhesion scores than patients with only black, white, and/or clear lesions. Oxiplex/AP gel was effective in reducing adhesions, compared to surgery alone, in all groups.

Proteomics. 2007 Jan;7(1):130-42.

An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: a heterogeneous tissue with a complex disease.

Fowler PA, Tattum J, Bhattacharya S, Klonisch T, Hombach-Klonisch S, Gazvani R, Lea RG, Miller I, Simpson WG, Cash P.

Department of Obstetrics & Gynaecology, University of Aberdeen, Aberdeen, UK. p.a.fowler@abdn.ac.uk

The pathogenesis of endometriosis includes the proliferation of heterogeneous endometrial cells and their invasion into ectopic sites within the peritoneal cavity. This may be due to abnormalities of the eutopic endometrium itself, predisposing the cells to survive and implant ectopically. We investigated the applicability of 2-DE gels and peptide mass mapping to identify candidate endometrial proteins with a role in endometriosis. Despite the heterogeneous nature of endometrium, our results show that combining the analysis of 2-DE gels and peptide mass mapping yields consistent data. We identified dysregulated proteins in women with endometriosis which included: (i) molecular chaperones including heat shock protein 90 and annexin A2, (ii) proteins involved in cellular redox state, such as peroxiredoxin 2, (iii) proteins involved in protein and DNA formation/breakdown, including ribonucleoside-diphosphate reductase, prohibitin and prolyl 4-hydroxylase, and (iv) secreted proteins, such as apolipoprotein A1. These proteins have functions which suggest that they could play a role in the pathogenesis of endometriosis. This study demonstrated that 2-DE gel analysis and mass spectroscopic protein identification are suitable for the identification of proteins with candidate associations with endometriosis. These techniques should be used on a larger scale to identify endometriosis-related proteins, thus improving the understanding of this complex disease.

Fertil Steril. 2007 Mar;87(3):619-26. Epub 2006 Nov 21.

Possible role of the plasminogen activation system in human subfertility.

Ebisch IM, Steegers-Theunissen RP, Sweep FC, Zielhuis GA, Geurts-Moespot A, Thomas CM.

Department of Obstetrics and Gynecology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

OBJECTIVE: To correlate components of the plasminogen activator (PA) system with fertility outcome parameters in participants in an IVF/intracytoplasmic sperm injection (ICSI) procedure. DESIGN: Case-control study. SETTING: Outpatient clinic for IVF/ICSI treatment at the Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. PATIENT(S): One hundred and fifty-six couples undergoing an IVF/ICSI procedure. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and t-PA-PAI-1 complex concentrations in the ejaculate, spermatozoa, and follicular fluid (FF). RESULT(S): Concentrations of t-PA were higher in spermatozoa of the male factor subfertility group (geometrical mean, 77.1 pg/million spermatozoa; 25th-75th percentiles, 31.8-211.2), compared to fertile men (geometrical mean, 1.91; 25th-75th percentiles, 0.74-5.79) and idiopathic subfertile men (geometrical mean, 3.14; 25th-75th percentiles, 0.97-9.97). Furthermore, the concentration of t-PA in spermatozoa was significantly associated with pregnancy (odds ratio [OR], 0.995). Likewise, a trend was shown for higher t-PA concentrations in the FF of women with fallopian-tube pathology (geometrical mean, 18.5 pg t-PA/mg protein; 25th-75th percentiles, 11.4-25.7) or endometriosis (geometrical mean, 18.8; 25th-75th percentiles, 11.4-27.1), compared to fertile women (geometrical mean, 14.3; 25th-75th percentiles, 10.3-17.6) and idiopathic subfertile women (geometrical mean, 13.9; 25th-75th percentiles, 9.5-17.8). Also, t-PA in FF is associated with the proportion of cleaved embryos (regression coefficient, 0.16). The concentrations of u-PA, PAI-1, and t-PA-PAI-1 complex were comparable between diagnostic subgroups in both men and women. CONCLUSION(S): The t-PA concentrations in spermatozoa and FF tend to be higher in human subfertility, and seem to be associated with some fertility outcome parameters.

Mol Hum Reprod. 2007 Feb;13(2):117-22. Epub 2006 Nov 22.

Estrogen receptor alpha-351 XbaI*G and -397 PvuII*C-related genotypes and alleles are associated with higher susceptibilities of endometriosis and leiomyoma.

Hsieh YY, Wang YK, Chang CC, Lin CS.

Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung and Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.

Endometriosis and leiomyoma are both common estrogen-related gynaecological diseases. We aimed to elucidate the association of estrogen receptor alpha (ERalpha)-351 A>G (XbaI) and -397 T>C (PvuII) gene polymorphisms with endometriosis and leiomyoma. Women were divided into three groups: (i) severe endometriosis (n = 112), (ii) leiomyoma (n = 106) and (iii) normal controls (n = 110). Genomic DNA was obtained from peripheral leukocytes. ERalpha-351 A/G XbaI and -397 T/C PvuII polymorphisms were assayed by the method of PCR and restriction fragment length polymorphism (RFLP). Genotypes and allelic frequencies in each group were compared. The genotype/allele frequencies of ERalpha-351 and -397 polymorphisms in endometriosis or leiomyoma groups were different from those of normal controls. ERalpha mutant-related genotypes/alleles (-351G and -397C) presented higher percentages in the endometriosis/leiomyoma population compared with normal controls. Proportions of ERalpha-351 AA/AG/GG genotypes and A/G alleles in each group were (i) 26.8/57.1/16.1 and 55.4/44.6%; (ii) 19.8/52.8/27.4 and 46.2/53.8% and (iii) 33.6/64.6/1.8 and 65.9/34.1%. Proportions of ERalpha-397 TT/TC/CC genotypes and T/C alleles in each group were (i) 24.1/60.7/15.2 and 54.5/45.5%; (ii) 23.6/70.8/5.6 and 59/41% and (iii) 54.5/40/5.5 and 74.5/25.5%. We concluded that ERalpha-351 XbaI*G- and -397 PvuII*C-related genotypes/alleles were correlated with higher susceptibilities of endometriosis or leiomyoma, which might be associated with related pathogeneses.

Eur Radiol. 2007 Jul;17(7):1813-9. Epub 2006 Nov 22.

Cine MR imaging of uterine peristalsis in patients with endometriosis.

Kido A, Togashi K, Nishino M, Miyake K, Koyama T, Fujimoto R, Iwasaku K, Fujii S, Hayakawa K.

Department of Diagnostic Imaging and Nuclear Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. akikido@kuhp.kyoto-u.ac.jp

Endometriosis is one of the most important causes of infertility; however the precise mechanism by which it affects female fertility is unclear. The objective of this study was to study the functional aspects of the uterus by evaluating uterine contractility in patients with endometrial cysts of the ovary. The study population was recruited from two institutes and consisted of 26 women (periovulatory (10), luteal (13), and menstrual phase (3); age range: 19-51 years) with untreated endometriosis; the control group consisted of 12 healthy women (age range: 22-41 years). Cine MR imaging obtained by a 1.5T magnet was visually evaluated at 12x faster than real speed, focusing on the presence of uterine peristalsis, the direction and frequency of peristalsis, and the presence of sustained uterine contractions. Uterine peristalsis was identifiable in 3/10, 3/13, and 3/3 of the endometriosis patients in each menstrual cycle, respectively, and in 11/12, 3/12, and 5/12 of their control subjects. Peristaltic detection rate and frequency were significantly less for the endometriosis group than for the controls in the periovulatory phase only (p<0.05). Sustained contractions were recognized in 19/36 control subjects and in 13/26 endometriosis patients, but the difference was not significant. Uterine peristalsis appears to be suppressed during the periovulatory phase in patients with endometriosis, which may have an adverse effect on sperm transport.

Hernia. 2007 Apr;11(2):175-7. Epub 2006 Nov 22.

Endometriosis mimicking hernia recurrence.

Ducarme G, Uzan M, Poncelet C.

Department of Obstetrics and Gynecology, Assistance Publique, Hôpitaux de Paris, CHU Jean Verdier, Avenue du 14 Juillet, 93140, Bondy, France. g.ducarme@gmail.com

Endometriosis is a common gynecologic condition and has been described in several locations, mostly in the pelvis. Extragenital endometriosis may appear as a painful nodule evoking an inguinal hernia. Scar endometriosis after inguinal hernia repair seems to be a rare occurrence. We report an unusual case of a 28-year-old woman who developed a scar endometriosis 2 years after an inguinal hernia repair. This case highlights that the presence of a painless inguinal mass similar to a recurrent hernia, with possible swelling related to the menstrual cycle, may evoke endometriosis, especially after a previous hernia repair and should lead to prompt diagnosis, wide excision, and gynecological advice.

Fertil Steril. 2007 Mar;87(3):698-701. Epub 2006 Nov 21.

Effect of the immunomodulator leflunomide on the induction of endometriosis in an experimental rat model.

Aytan H, Caglar P, Uygur D, Zergeroglu S, Batioglu S.

The effect of immunomodulator leflunomide on the development of an experimental endometriosis model was assessed by surgically transplanting autologous fragments of endometrial tissue onto the inner surface of the abdominal wall and arterial cascades of the small intestines. Leflunomide was found to affect the development of endometriosis negatively and seemed to interfere with the growth and maintenance of the uterine explant in this experimental rat model.

Am J Epidemiol. 2007 Feb 1;165(3):325-33. Epub 2006 Nov 16.

Receiver operating characteristic curve inference from a sample with a limit of detection.

Perkins NJ, Schisterman EF, Vexler A.

Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

The receiver operating characteristic curve is a commonly used tool for evaluating biomarker usefulness in clinical diagnosis of disease. Frequently, biomarkers being assessed have immeasurable or unreportable samples below some limit of detection. Ignoring observations below the limit of detection leads to negatively biased estimates of the area under the curve. Several correction methods are suggested in the areas of mean estimation and testing but nothing regarding the receiver operating characteristic curve or its summary measures. In this paper, the authors show that replacement values below the limit of detection, including those suggested, result in the same biased area under the curve when properly accounted for, but they also provide guidance on the usefulness of these values in limited situations. The authors demonstrate maximum likelihood techniques leading to asymptotically unbiased estimators of the area under the curve for both normally and gamma distributed biomarker levels. Confidence intervals are proposed, the coverage probability of which is scrutinized by simulation study. An example using polychlorinated biphenyl levels to classify women with and without endometriosis illustrates the potential benefits of these methods.

Surg Endosc. 2007 Jun;21(6):916-9. Epub 2006 Nov 14.

Impact of diagnostic laparoscopy on the management of chronic pelvic pain.

Kang SB, Chung HH, Lee HP, Lee JY, Chang YS.

Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, Korea. ksboo308@snu.ac.kr

BACKGROUND: Diagnostic laparoscopy is a useful tool, especially when there is no definite anatomical abnormality visible on imaging modalities. We assess the role and clinical impact of diagnostic laparoscopy in the management of women with chronic pelvic pain. METHODS: Clinical data of 3,068 cases of diagnostic laparoscopy performed for chronic pelvic pain from June 1994 to August 2005 were analyzed. We compared the diagnoses after diagnostic laparoscopy and those after pelvic examination and imaging modalities such as ultrasound or computed tomography (CT), and we then checked the final pathologic diagnoses after operation. RESULTS: Pelvic endometriosis was the most common (60.2%) laparoscopic finding in patients with chronic pelvic pain in this study, followed by normal pelvic findings (21.2%) and pelvic congestion (13.0%). Diagnostic laparoscopy had an influence on correcting previous plans based on imaging modalities in 42.7% of patients such as discarding unnecessary procedures or introducing new diagnostic or therapeutic plans. There were 3 cases of major complications requiring immediate correction. CONCLUSIONS: Diagnostic laparoscopy is a useful diagnostic tool for of women with chronic pelvic pain and can be used as a guideline for individualized treatment.

Fertil Steril. 2007 Feb;87(2):257-62. Epub 2006 Nov 13.

Effect of a statin on an in vitro model of endometriosis.

Esfandiari N, Khazaei M, Ai J, Bielecki R, Gotlieb L, Ryan E, Casper RF.

Toronto Centre for Advanced Reproductive Technology, Department of Obstetrics and Gynecology, Division of Reproductive Sciences, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

OBJECTIVE: To determine the inhibitory effect of a statin on angiogenesis in a three-dimensional (3-D) culture of human endometrial fragments in vitro. Angiogenesis has been proposed as an important mechanism in the pathogenesis of endometriosis, and statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) have been shown to have anti-inflammatory and anti-angiogenic activity. DESIGN: Experimental in vitro study of human endometrial biopsies and 3-D culture in fibrin matrix. SETTING: Research laboratory at a university-affiliated infertility center. PATIENT(S): Forty-six normal ovulating women undergoing infertility treatment. INTERVENTION(S): Endometrial samples obtained from the fundus of the uterine cavity were minced, and the fragments were placed in a three-dimensional fibrin matrix culture system. MAIN OUTCOME MEASURE(S): Presence or absence of proliferation of stromal cells and invasion of the fibrin matrix, presence or absence of vessel sprouting, and immunohistochemical characterization of cellular components. RESULT(S): During the 1st week of culture, invasion of stromal cells into the fibrin matrix occurred in the control group and in some wells outgrowths were observed. After 2 weeks, endometrial glands were observed in the outgrowths at a distance from the main tissue and were growing in conjunction with new vessel formation until the end of culture period. A concentration-dependent effect of lovostatin was seen on cell growth and angiogenesis in the experimental groups. In the presence of 5 and 10 microM of statin, angiogenesis was abolished, and cell proliferation was inhibited. In the presence of 1 microM of lovastatin, angiogenesis was reduced, but cell proliferation was not affected. CONCLUSION(S): The statins were shown to be effective in inhibiting the mechanisms of cell proliferation and angiogenesis in an experimental model for the development of endometriosis-like tissue.

Endocrinology. 2007 Feb;148(2):857-67. Epub 2006 Nov 9.

Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902.

Struthers RS, Xie Q, Sullivan SK, Reinhart GJ, Kohout TA, Zhu YF, Chen C, Liu XJ, Ling N, Yang W, Maki RA, Bonneville AK, Chen TK, Bozigian HP.

Department of Endocrinology, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, California 92130, USA. sstruthers@neurocrine.com

Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K(i) = 0.56 nm). Tritiated NBI-42902 binds with high affinity (K(d) = 0.19 nm) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated IP accumulation, Ca(2+) flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.

Fertil Steril. 2007 Feb;87(2):362-6. Epub 2006 Nov 13.

Comment in:

Fertil Steril. 2007 Aug;88(2):534; author reply 534-5.

Fertil Steril. 2007 Oct;88(4):1017-8; author reply 1018-9.

Histologic analysis of endometriomas: what the surgeon needs to know.

Muzii L, Bianchi A, Bellati F, Cristi E, Pernice M, Zullo MA, Angioli R, Panici PB.

Department of Obstetrics and Gynecology, University Campus Bio-Medico of Rome, Rome, Italy. l.muzii@unicampus.it <l.muzii@unicampus.it>

OBJECTIVE: To evaluate by thorough pathologic analysis the histologic features of the endometrioma wall excised at laparoscopy. DESIGN: Prospective series of consecutive patients. SETTING: Tertiary care, university hospital. PATIENT(S): Fifty-nine patients with ovarian endometriomas. A total of 70 cysts were examined. INTERVENTION(S): Patients underwent operative laparoscopy with the stripping technique for excision of the ovarian endometrioma. MAIN OUTCOME MEASURE(S): A thorough histologic examination was performed on the entire cyst wall specimen. RESULT(S): Histologic examination confirmed the endometriotic nature of the cyst in 100% of the cases. The inner wall of the endometrioma was covered by endometriotic tissue on 60% of the surface. The mean cyst wall thickness was 1.4 mm. The mean value of maximal depth of endometriosis penetration in the endometrioma wall was 0.6 mm. In 99% of the cases the maximal penetration of the endometriotic tissue was <1.5 mm. CONCLUSION(S): In the present study, we demonstrate that the endometrioma wall contains endometriotic tissue in 100% of the cases. However, the endometriotic tissue may cover the inner cyst wall for a surface that varies between 10% and 98% of the entire wall (median value 60%). This tissue may reach a depth of 2 mm, but for most of the surface it does not penetrate >1.5 mm. These histologic data may help the gynecologic laparoscopist select the surgical approach that maximally preserves healthy ovarian tissue.

Fertil Steril. 2007 Feb;87(2):419-21. Epub 2006 Nov 7.

Lateral distribution of endometriomas as a function of age.

Bazi T, Abi Nader K, Seoud MA, Charafeddine M, Rechdan JB, Zreik TG.

Department of Obstetrics and Gynecology, American University of Beirut, Beirut, Lebanon.

The lateral asymmetry of ovarian endometriomas, with a left-sided predilection, seems to disappear with advancing age. This asymmetry does not seem to persist in women >35 years of age.

Fertil Steril. 2007 Feb;87(2):263-8. Epub 2006 Nov 13.

Quantitative expression of apoptosis-regulating genes in endometrium from women with and without endometriosis.

Braun DP, Ding J, Shaheen F, Willey JC, Rana N, Dmowski WP.

Cancer Institute, Departments of Surgery and Medicine, Medical University of Toledo, Toledo, Ohio 43614-5809, USA. donald.braun@ctca-hope.com

OBJECTIVE: To quantitate antiapoptotic and proapoptotic gene expression in endometrial cells (ECs) of women with and without endometriosis. DESIGN: Determination of transcript abundance (TA) of apoptosis-regulating genes in eutopic and ectopic endometrial cells. SETTING: Institute for the Study and Treatment of Endometriosis, Chicago, Illinois, and university-based research laboratories. PATIENT(S): Women with (n = 10) and without (n = 6) endometriosis. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Quantitative virtually multiplexed transcript abundance measurement (VMTA) of the BCL2, BCLxL, defender against cell death-1 (DAD-1), BCLxS, P53, Caspase-1, and proliferating cell nuclear antigen (PCNA) genes. RESULT(S): The TA ratio of antiapoptotic to proapoptotic isoforms of the BCL-X gene favors survival in eutopic and ectopic ECs from women with endometriosis, but not control ECs. This was found throughout the menstrual cycle for ectopic ECs. Eutopic but not ectopic ECs also expressed increased TA of the antiapoptotic DAD-1 gene in endometriosis. Eutopic and ectopic ECs from women with endometriosis expressed decreased TA of p53 and Caspase-1 compared to ECs from women without endometriosis. Expression of these genes was not correlated with the proliferative state of ECs based on TA of the PCNA gene. CONCLUSION(S): Dysregulation in expression of pro- and antiapoptotic regulatory genes characterizes eutopic and ectopic ECs from women with endometriosis. These results are consistent with apoptotic resistance and enhanced survival of ECs in endometriosis.

Hum Reprod. 2007 Mar;22(3):644-53. Epub 2006 Nov 8.

Effect of GnRH analogues on apoptosis and expression of Bcl-2, Bax, Fas and FasL proteins in endometrial epithelial cell cultures from patients with endometriosis and controls.

Bilotas M, Barañao RI, Buquet R, Sueldo C, Tesone M, Meresman G.

Instituto de Biología y Medicina Experimental, Hospital de Clínicas José de San Martín, Buenos Aires, Argentina. mabilotas@dna.uba.ar

BACKGROUND: Our purpose was to evaluate the effect of the GnRH agonist (GnRHa), leuprolide acetate (LA), and the GnRH antagonist (GnRHant), Antide, on apoptosis and expression of apoptosis-related proteins in endometrial epithelial cell (EEC) cultures from patients with endometriosis and controls (infertile women without endometriosis). METHODS: Biopsy specimens of eutopic endometrium were obtained from 22 patients with endometriosis and from 14 women that served as controls. Apoptosis was examined in EEC after incubation with LA and Antide. Bax, Bcl-2, Fas and FasL expression was evaluated after exposure to LA, Antide or a combination of both. The percentage of apoptotic cells (%ApC) was assessed by the acridine orange-ethidium bromide technique, and protein expression was evaluated by western blot and immunocytochemistry. RESULTS: LA 100 and 1000 ng/ml increased the %ApC in EEC from patients with endometriosis (both P < 0.05) and controls (p < 0.05 and P < 0.01, respectively). Antide 10(-5) M increased the %ApC in EEC from patients with endometriosis and controls (P < 0.01). In EEC from women with endometriosis, Bax expression increased after treatment with LA, Antide and LA + Antide (P < 0.05, P < 0.001 and P < 0.001), whereas Bcl-2 expression decreased after exposure to LA and Antide (P < 0.001 and P < 0.01). FasL expression increased after LA, Antide and LA + Antide treatments (P < 0.01, P < 0.001 and P < 0.01). No significant changes were observed on Fas expression. CONCLUSIONS: GnRH analogues enhanced apoptosis in EEC, and this was accompanied by an increase in expression of the pro-apoptotic proteins Bax and FasL and a decrease in expression of the anti-apoptotic protein Bcl-2.

J Thromb Haemost. 2007 Mar;5(3):503-6. Epub 2006 Nov 9.

The incidence of venous thromboembolism following gynecologic laparoscopy: a multicenter, prospective cohort study.

Ageno W, Manfredi E, Dentali F, Silingardi M, Ghezzi F, Camporese G, Bolis P, Venco A.

Department of Clinical Medicine, University of Insubria, Varese, Italy. agewal@yahoo.com

BACKGROUND: Information on the incidence of venous thromboembolism (VTE) following laparoscopic procedures is inadequate and there is currently no solid evidence to guide the use of thromboprophylaxis in this setting. Gynecologic laparoscopy is a common procedure, and is frequently performed in low-risk patients. To our knowledge, there are no clinical studies specifically designed to assess the incidence of VTE in this setting. METHODS: In a prospective cohort study, consecutive patients undergoing gynecologic laparoscopy underwent compression ultrasonography (CUS) and clinical assessment to evaluate the incidence of clinically relevant VTE. CUS was performed 7 +/- 1 and 14 +/- 1 days postoperatively. A subsequent telephone contact was scheduled at 30 and 90 days. No patient received pharmacologic or mechanical prophylaxis. Patients with malignancy or previous VTE were excluded from the study. RESULTS: We enrolled 266 consecutive patients; mean age was 36.3 years, range: 18-72. The most common indications for laparoscopy were ovarian cysts in 25.6% of patients, endometriosis in 21.0% of patients, unexplained adnexal masses in 12.4% of patients, and infertility in 7.5% of patients. The mean duration of the procedure was 60.5 min (range: 10-300 min). In particular, in 55.6% of patients the duration exceeded 45 min. There were neither episodes of CUS detected DVT (0/247; 0%, 95% CI 0-1.51%) or clinically relevant VTE after follow-up (0/256; 0%, 95% CI 0-1.48%). No patient died of fatal pulmonary embolism (0/266; 0%, 95% CI 0-1.42%). CONCLUSIONS: Gynecologic laparoscopy in non-cancer patients is a low-risk procedure for postoperative VTE.

Fertil Steril. 2007 Jan;87(1):163-71. Epub 2006 Nov 1.

Selective cyclo-oxygenase-2 inhibition induces regression of autologous endometrial grafts by down-regulation of vascular endothelial growth factor-mediated angiogenesis and stimulation of caspase-3-dependent apoptosis.

Laschke MW, Elitzsch A, Scheuer C, Vollmar B, Menger MD.

Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany. matthias.laschke@uniklinik-saarland.de <matthias.laschke@uniklinik-saarland.de>

OBJECTIVE: To investigate the effects of selective cyclo-oxygenase-2 (COX-2) inhibition on the angiogenesis and proliferation of endometrial grafts. DESIGN: Intravital fluorescence microscopic study. SETTING: Institute for Clinical and Experimental Surgery, University of Saarland, Homburg/Saar, Germany. ANIMALS: Syrian golden hamsters. INTERVENTIONS: Endometrial fragments were transplanted into dorsal skinfold chambers of Syrian golden hamsters. Animals were treated daily with the selective COX-2-inhibitor NS398; controls received the vehicle dimethyl sulfoxide only. MAIN OUTCOME MEASURES: Angiogenesis was analyzed for 2 weeks with the use of intravital fluorescence microscopy. Protein expression of vascular endothelial growth factor, proliferating cell nuclear antigen, caspase-3, and activated caspase-3 was measured by Western blot analysis. Histological sections were scanned for local microthrombosis. RESULTS: COX-2 inhibition induced a marked regression of endometrial grafts due to inhibition of angiogenesis, as indicated by significantly reduced microvessel density within grafts compared to controls. This effect was associated with a decreased expression of vascular endothelial growth factor. Moreover, COX-2 inhibition suppressed cell proliferation and induced apoptosis-associated caspase-3 expression. Interestingly, microthrombus formation could not be observed. CONCLUSIONS: Our study demonstrates that selective COX-2 inhibition induces regression of endometrial grafts by suppression of angiogenesis and stimulation of apoptosis. Accordingly, COX-2 inhibition may represent a novel therapeutic strategy for the treatment of endometriosis.

Fertil Steril. 2007 Jan;87(1):24-32. Epub 2006 Nov 1.

Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis.

Wu Y, Strawn E, Basir Z, Halverson G, Guo SW.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226-0509, USA.

OBJECTIVE: Since endometriosis is a persistent disease with substantial gene dysregulation, there must be cellular memory of some sort that constitutes a unique cell identity for endometriotic cells. Epigenetic regulation, especially through DNA methylation, is a flexible, yet stable, mechanism for maintaining such a cellular memory. The aim of this study was to determine gene expression levels of DNMT1, DNMT3A, and DNMT3B, the three genes coding for DNA methyltransferases that are responsible for methylation. DESIGN: Cross-sectional measurements of gene expression levels of DNMT1, DNMT3A, and DNMT3B on endometriotic tissue. SETTING: Academic. PATIENT(S): Seventeen patients with laparoscopically confirmed endometriosis and 8 healthy women who underwent tubal sterilization who were free of endometriosis were recruited for the study. INTERVENTION(S): Epithelial cells were harvested from tissue samples by laser capture microdissection and messenger RNA abundance was measured by quantitative real-time reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): The expression levels of these genes in epithelial cells from 13 ectopic endometrial tissue samples, 10 eutopic endometrial tissue samples taken from women with endometriosis, and 8 normal endometrial tissue samples from women without endometriosis. RESULT(S): The genes DNMT1, DNMT3A, and DNMT3B were over-expressed in the ectopic endometrium as compared with normal control subjects or the eutopic endometrium of women with endometriosis, and their expression levels were correlated positively with each other. CONCLUSION(S): The aberrant expression of these genes suggests that aberrant methylation may be rampant in endometriosis. This also provides a strong piece of evidence that endometriosis ultimately may be an epigenetic disease.

Fertil Steril. 2007 Jan;87(1):227-9. Epub 2006 Nov 1.

Dyspareunia and quality of sex life after laparoscopic excision of endometriosis and postoperative administration of triptorelin.

Ferrero S, Abbamonte LH, Parisi M, Ragni N, Remorgida V.

Department of Obstetrics and Gynecology, San Martino Hospital, University of Genoa, Genoa, Italy. simone.ferrero@fastwebnet.it <simone.ferrero@fastwebnet.it>

This observational cohort study examined the effect of laparoscopic full excision of endometriosis combined with postoperative triptorelin treatment on deep dyspareunia (DD) and quality of sex life. One year after completing the postoperative treatment, 45.9% of the patients had no DD and 34.7% reported a decrease in DD intensity; an increase in the frequency of sexual intercourse was reported by 62.2% of the women; objective improvements in several aspects of sex life were observed.

J Reprod Dev. 2007 Feb;53(1):87-94. Epub 2006 Nov 1.

Effect of danazol on NK cells and cytokines in the mouse uterus.

Kusakabe K, Morishima S, Nakamuta N, Li ZL, Otsuki Y.

Department of Anatomy and Cell Biology, Division of Basic Medicine 1, Osaka Medical College, Japan.

Danazol, which has been used as a medicine for endometriosis, has a valid effect in pretreatment of patients receiving in vitro fertilization and embryo transfer, although its reproductive mechanism remains unclear. BALB/c mice were subcutaneously injected with danazol for 2 weeks. Blood and uteri were collected and cytokines were assayed. Following danazol treatment, an increase in pregnancy ratio was evident that was accompanied by up-regulation in serum macrophage-colony stimulating factor (M-CSF). RT-PCR analysis revealed that expression of M-CSF and Ly49, a phenotypic marker of natural killer (NK) cells, was up-regulated in the uteri of the danazol-treated mice. In immunohistochemical analysis, M-CSF and Ly49, together with alpha5 integrin, were clearly detected in the endometrium of the danazol-treated mice with very similar pattern of localization. These results suggest that danazol has an effect to promote pregnancy that induces recruitment of NK cells and a concomitant increase in the expression of M-CSF and alpha5 integrin in the uterus.

Hum Reprod. 2007 Mar;22(3):843-9. Epub 2006 Oct 31.

Increased telomerase activity and human telomerase reverse transcriptase mRNA expression in the endometrium of patients with endometriosis.

Kim CM, Oh YJ, Cho SH, Chung DJ, Hwang JY, Park KH, Cho DJ, Choi YM, Lee BS.

Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Yongdong Severance Hospital, Seoul, Korea.

BACKGROUND: Endometriosis is considered a frequent, benign disease with the ability to undergo neoplastic processes. The aim of this study was to evaluate the limitless replication potential of the endometrium in patients with endometriosis by examining human telomerase reverse transcriptase (hTERT) mRNA expression and telomerase activity. METHODS: Endometrium samples from 30 endometriosis patients and 30 patients without endometriosis were obtained via endometrial biopsy. The expression of hTERT mRNA was determined by real-time RT-PCR assay, and telomerase activity was measured by telomerase repeat amplification protocol (TRAP) assay. RESULTS: The mean normalized hTERT (N hTERT) mRNA level was significantly higher in the endometriosis than in the control group (P = 0.013). The mean hTERT mRNA levels during the proliferative phase and during the secretory phase were higher in the endometriosis group than in the control group, although the difference was only significant for the secretory phase (P = 0.036). We found a prominent difference in endometrial telomerase activity between moderate-to-severe endometriosis and the control group (P = 0.048). The levels of hTERT mRNA and telomerase activity increased as the disease became more severe (P = 0.038, P = 0.016). CONCLUSIONS: This study showed the overexpression of hTERT mRNA and telomerase activity in the endometrium of endometriosis patients. These finding suggest that replication potential of endometrial cells may have an important role in the pathogenesis of endometriosis.

Hum Reprod. 2007 Mar;22(3):836-42. Epub 2006 Oct 24.

Serum interleukin-6 levels are elevated in women with minimal-mild endometriosis.

Martínez S, Garrido N, Coperias JL, Pardo F, Desco J, García-Velasco JA, Simón C, Pellicer A.

Department of Obstetrics and Gynecology, Hospital Universitario Dr Peset, University of Valencia, Spain.

BACKGROUND: There is a need for a reliable marker of endometriosis, especially in early stages of peritoneal disease during which imaging is not effective. The use of serum interleukin (IL)-6 as a marker is controversial. To readdress the matter, patients undergoing laparoscopy were prospectively evaluated for serum IL-6 levels. MATERIALS AND METHODS: A total of 119 women 31 years old who underwent laparoscopy were divided into groups: control patients (n = 38) with no pathologic findings; endometriosis sufferers (n = 47) with minimal-mild (MM, n = 11) or moderate-severe (MS, n = 36) endometriosis; uterine myomas (n = 13) and benign ovarian pathologies (n = 21). Blood was drawn on cycles days 5-12 and stored for subsequent analysis of IL-6 and carbohydrate antigen (CA)-125 levels. RESULTS: Serum IL-6 levels were significantly (P = 0.002) higher in women with MM endometriosis (29.4 9.0 pg/ml) than in controls (15.7 9.3 pg/ml). When all the non-endometriosis patients were grouped together (n = 72) and serum IL-6 (17.8 12.1 pg/ml) compared with MS (n = 36; 17.6 10.3 pg/ml) and MM (n = 11; 29.4 9.0 pg/ml) endometriosis significantly (P < 0.01) higher levels in MM endometriosis were observed as compared to the other two groups. Serum Ca-125 levels were significantly (P < 0.01) elevated in MS endometriosis. A serum IL-6 threshold of 25.75 pg/ml afforded a sensitivity of 75% and specificity of 83% in the diagnosis of MM endometriosis. Sensitivity and specificity for CA-125 in the diagnosis of MS endometriosis, using 35 IU/ml as the cut-off value, were 47% and 97%, respectively. CONCLUSIONS: IL-6 is a reliable non-invasive marker of MM endometriosis, whereas Ca-125 is of use as a marker of severe cases.

Gynecol Obstet Invest. 2007;63(3):140-2. Epub 2006 Oct 19.

Mixed clear cell and endometrioid carcinoma arising in parietal endometriosis.

Razzouk K, Roman H, Chanavaz-Lacheray I, Scotté M, Verspyck E, Marpeau L.

Department of Gynecology and Obstetrics, University Hospital, Rouen, France.

AIM: We report a case of a mixed clear cell and endometrioid carcinoma arising in parietal endometriosis. METHODS: A 46-year-old woman presented a second recurrence of parietal endometriosis. An extensive surgical resection of the tumor was then carried out. RESULTS: Histological analysis revealed heterogeneous tissues including clear cell and endometrioid carcinoma fields arising from a large benign endometriosis lesion. Despite chemotherapy, the patient died 6 months after the diagnosis. CONCLUSIONS: Clear cell carcinoma and endometrioid carcinoma have been rarely found in parietal endometriosis. Clinicians should learn to suspect a cancerous transformation of a parietal endometriosis, when rapid recurrence and extensive development are observed. Copyright (c) 2007 S. Karger AG, Basel.

Reprod Toxicol. 2007 Apr-May;23(3):326-36. Epub 2006 Sep 30.

Developmental exposure of mice to TCDD elicits a similar uterine phenotype in adult animals as observed in women with endometriosis.

Nayyar T, Bruner-Tran KL, Piestrzeniewicz-Ulanska D, Osteen KG.

Women’s Reproductive Health Research Center, Department of Obstetrics & Gynecology, Vanderbilt University School of Medicine, 1161 21st Avenue S, MCN B-1100, Nashville, TN 37232, USA.

Whether environmental toxicants impact an individual woman’s risk for developing endometriosis remains uncertain. Although the growth of endometrial glands and stroma at extra-uterine sites is associated with retrograde menstruation, our studies suggest that reduced responsiveness to progesterone may increase the invasive capacity of endometrial tissue in women with endometriosis. Interestingly, our recent studies using isolated human endometrial cells in short-term culture suggest that experimental exposure to the environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the expression of progesterone receptor isotypes. Compared to adult exposure, toxicant exposure during development can exert a significantly greater biological impact, potentially affecting the incidence of endometriosis in adults. To address this possibility, we exposed mice to TCDD at critical developmental time points and subsequently examined uterine progesterone receptor expression and steroid responsive transforming growth factor-beta2 expression in adult animals. We find that the uterine phenotype of toxicant-exposed mice is markedly similarly to the endometrial phenotype of women with endometriosis.

Langenbecks Arch Surg. 2007 Jan;392(1):105-9. Epub 2006 Oct 17.

Scar endometriosis – a gynaecologic pathology often presented to the general surgeon rather than the gynaecologist: report of two cases.

Aydin O.

Department of Pathology, Alanya Hospital, Başkent University, Alanya, Antalya, Turkey. darkeetar@yahoo.com

INTRODUCTION: Scar endometriosis develops in and is adjacent to surgical scars at the site of previous abdominal operations. The most frequent clinical presentation of the disease is that of a palpable subcutaneous mass near surgical scars associated with cyclic pain and swelling during menses. Endometriosis of the surgical scar is often referred to the general surgeons because the clinical presentation suggests an incisional hernia or other conditions related to the general surgery. Cyclical symptoms such as pain and swelling, in relation to surgical scars, which worsen at the time of menstruation, are nearly pathognomonic of scar endometriosis. However, often the diagnosis of endometriosis is not suggested until after histology has been performed. CASE REPORT: We present two cases of cutaneous endometriosis that has occurred on the site of previous cesarean section scar area.

Gynecol Obstet Invest. 2007;63(2):71-97. Epub 2006 Oct 4.

Nuclear factor-kappab (NF-kappaB): an unsuspected major culprit in the pathogenesis of endometriosis that is still at large?

Guo SW.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226-0509, USA. swguo@mcw.edu

Endometriosis, defined as the ectopic presence of endometrial glandular and stromal cells outside the uterine cavity, is a common benign gynecological disorder with an enigmatic pathogenesis. Many genes and gene products have been reported to be altered in endometriosis, yet some of them may not be major culprits but merely unwitting accomplices or even innocent bystanders. Therefore, the identification and apprehension of major culprits in the pathogenesis of endometriosis are crucial to the understanding of the pathogenesis and would help to develop better therapeutics for endometriosis. Although so far NF-kappaB only has left few traces of incriminating fingerprints, several lines of investigation suggest that NF-kappaB, a pivotal pro-inflammatory transcription factor, could promote and maintain endometriosis. Various inflammatory agents, growth factors, and oxidative stress activate NF-kappaB. NF-kappaB proteins themselves and proteins regulated by them have been linked to cellular transformation, proliferation, apoptosis, angiogenesis, and invasion. Interestingly, all existing and nearly all investigational medications for endometriosis appear to act through suppression of NF-kappaB activation. In endometriotic cells, NF-kappaB appears to be constitutively activated, and suppression of NF-kappaB activity by NF-kappaB inhibitors or proteasome inhibitors suppresses proliferation in vitro. Viewing NF-kappaB as a major culprit, an autoregulatory loop model can be postulated, which is consistent with existing data and, more importantly, can explain several puzzling phenomena that are otherwise difficult to interpret based on prevailing theories. This view has immediate and important implications for novel ways to treat endometriosis. Further research is warranted to precisely delineate the roles of NF-kappaB in the pathogenesis of endometriosis and to indict and convict its aiders and abettors.

Gynecol Obstet Invest. 2007;63(2):107-13. Epub 2006 Oct 6.

The obstetrical history in patients with Pfannenstiel scar endometriomas–an analysis of 81 patients.

Wicherek L, Klimek M, Skret-Magierlo J, Czekierdowski A, Banas T, Popiela TJ, Kraczkowski J, Sikora J, Oplawski M, Nowak A, Skret A, Basta A.

Department of Gynecology and Infertility, Jagiellonian University, Krakow, Poland. mowicher@cyf-kr.edu.pl

INTRODUCTION: The participation of immune tolerance during pregnancy was suggested to be an important factor predisposing to the implantation of decidual cells after cesarean section in Pfannenstiel scar. Delivery at term is related to the termination of immune tolerance to fetal antigens that is maintained throughout pregnancy. Substantial proportion of cesarean section deliveries is performed before the onset of true term labor. The aim of this study was to analyze the clinical symptoms of spontaneous beginning of labor in pregnant women in whom cesarean sections were performed and in whom Pfannenstiel scar endometriomas were observed during follow-up. MATERIALS AND METHODS: We have retrospectively analyzed 81 patients following the surgical removal of scar endometrioma after cesarean section. Obstetrical histories of cesarean sections in the number of 5,370 preceding the occurrence of the scar endometrioma were analyzed. These data were collected in six different Gynecological and Obstetrical wards in Malopolska Province in Poland. Analysis of data was started by the retrospective evaluation of regular uterine contractions, uterine cervix ripening before cesarean section and the indications for surgery. RESULTS: In 67 women from the group of 81 patients cesarean sections were performed with unripe uterine cervix and without the presence of regular uterine contractions. Elective indications for cesarean sections were predominant in this group of women. The relative risk of scar endometriomas occurrence following cesarean sections performed before onset of labor in comparison to cesarean sections following spontaneous onset of labor was statistically significantly higher [RR = 2.16, 95% CI = 1.21-3.83; OR = 2.18, 95% CI = 1.22-3.89]. CONCLUSIONS: Cesarean section performed before spontaneous onset of labor may increase substantially the risk of occurrence of scar endometriomas.

Eur J Nucl Med Mol Imaging. 2007 Mar;34(3):354-62. Epub 2006 Sep 22.

Comment in:

Eur J Nucl Med Mol Imaging. 2007 Mar;34(3):346-53.

Targeted functional imaging of estrogen receptors with 99mTc-GAP-EDL.

Takahashi N, Yang DJ, Kohanim S, Oh CS, Yu DF, Azhdarinia A, Kurihara H, Zhang X, Chang JY, Kim EE.

Division of Diagnostic Imaging, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

PURPOSE: To evaluate the feasibility of using (99m)Tc-glutamate peptide-estradiol in functional imaging of estrogen receptor-positive [ER(+)] diseases. METHODS: 3-Aminoethyl estradiol (EDL) was conjugated to glutamate peptide (GAP) to yield GAP-EDL. Cellular uptake studies of (99m)Tc-GAP-EDL were conducted in ER(+) cell lines (MCF-7, 13762 and T47D). To demonstrate whether GAP-EDL increases MAP kinase activation, Western blot analysis of GAP-EDL was performed in 13762 cells. Biodistribution was conducted in nine rats with 13762 breast tumors at 0.5-4 h. Each rat was administered (99m)Tc-GAP-EDL. Two animal models (rats and rabbits) were created to ascertain whether tumor uptake of (99m)Tc-GAP-EDL was via an ER-mediated process. In the tumor model, breast tumor-bearing rats were pretreated with diethylstilbestrol (DES) 1 h prior to receiving (99m)Tc-GAP-EDL. In the endometriosis model, part of the rabbit uterine tissue was dissected and grafted to the peritoneal wall. The rabbit was administered with (99m)Tc-GAP-EDL. RESULTS: There was a 10-40% reduction in uptake of (99m)Tc-GAP-EDL in cells treated with DES or tamoxifen compared with untreated cells. Western blot analysis showed an ERK1/2 phosphorylation process with GAP-EDL. Biodistribution studies showed that tumor uptake and tumor-to-muscle count density ratio in (99m)Tc-GAP-EDL groups were significantly higher than those in (99m)Tc-GAP groups at 4 h. Among (99m)Tc-GAP-EDL groups, region of interest analysis of images showed that tumor-to muscle ratios were decreased in blocking groups. In the endometriosis model, the grafted uterine tissue could be visualized by (99m)Tc-GAP-EDL. CONCLUSION: Cellular or tumor uptake of (99m)Tc-GAP-EDL occurs via an ER-mediated process. (99m)Tc-GAP-EDL is a useful agent for imaging functional ER(+) disease.

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