BJOG. 2010 Nov 18. doi: 10.1111/j.1471-0528.2010.02774.x. [Epub ahead of print]

Complications after surgery for deeply infiltrating pelvic endometriosis.

Kondo W, Bourdel N, Tamburro S, Cavoli D, Jardon K, Rabischong B, Botchorishvili R, Pouly J, Mage G, Canis M.

Department of Gynaecologic Surgery, CHU Estaing, Clermont-Ferrand, France.

Please cite this paper as: Kondo W, Bourdel N, Tamburro S, Cavoli D, Jardon K, Rabischong B, Botchorishvili R, Pouly J, Mage G, Canis M. Complications after surgery for deeply infiltrating pelvic endometriosis. BJOG 2010; DOI:  To evaluate the complications after 10.1111/j.1471-0528.2010.02774.x. Objective  Data from  Retrospective study. Setting surgery for deep endometriosis. Design the CHU Estaing database and patients’ charts between January 1987 and December  All women given surgical treatment for deep endometriosis. 2007. Sample  Women who underwent surgery for deep endometriosis were reviewed for Methods  Primary outcomes intra- and postoperative complications. Main outcome measures were rates of intra- and postoperative complications. Complications were  A total of 568 women compared according to the procedure performed. Results years. The mean estimated were included in the study, with a mean age of 32.4 cm (ranging from 0.5 diameter of the nodule felt by vaginal examination was 1.8 cm). Laparoscopic surgery was performed in 560 women (98.6%), and to 7 minutes. conversion was required in 2.3%. The mean operative time was 155 Intraoperative complications occurred in 12 women (2.1%), including six minor (1.05%) and six major (1.05%) complications. Postoperative complications developed in 79 women (13.9%), including 54 minor (9.5%) and 26 major (4.6%) complications (one woman had both minor and major postoperative complications). The overall major postoperative complication rate for women who underwent any type of rectal surgery (shaving, excision and suture, or segmental resection) was 9.3% (21 out of 226), compared with only 1.5% for the other women (five out  of 342) (P<0.01). Shaving presented less major postoperative complications   0.004). Conclusions = compared with segmental resection (24 versus 6.7%; P Surgery for deep endometriosis is feasible, but it is associated with major complications, especially when any type of rectal surgery must be performed.

© 2010 The Authors Journal compilation © RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology.

J Obstet Gynaecol Res. 2010 Nov 18. doi: 10.1111/j.1447-0756.2010.01320.x. [Epub ahead of print]

Endometrioid ovarian cancer and endometriotic cells exhibit the same alteration in the expression of interleukin-1 receptor II: To a link between endometriosis and endometrioid ovarian cancer.

Keita M, Ainmelk Y, Pelmus M, Bessette P, Aris A.

Departments of Obstetrics and Gynecology Pathology Clinical Research Centre of Sherbrooke University Hospital Centre, Sherbrooke, Quebec, Canada.

Endometrioid carcinoma of the ovary is the third most common type of Aim: epithelial ovarian cancer. Endometrioid tumors as well as endometriotic implants are characterized by the presence of epithelial cells, stromal cells, or a combination of booth, that resemble the endometrial cells, suggesting a possible endometrial origin of these tumors. Th1 cytokines including interleukin (IL)-1 have been reported to be involved in both endometriosis and ovarian carcinogenesis. We assessed the expression of receptors of IL-1 (IL-1RI and IL-1RII, the signal transducer and the specific inhibitor of IL-1, respectively) in cells of the most common subtypes of ovarian cancer compared to endometrial cells. Material &  IL1-Rs expression was analyzed at the levels of Methods: the protein and mRNA using immunofluorescent and real-time polymerase chain  We showed that endometrioid cells reaction methods, respectively. Results: exhibit a specific decrease of IL-1RII expression, whereas IL-1RI was constantly  As already reported in expressed in all studied cell subtypes. Conclusion: endometriotic cells, endometrioid ovarian cancer cells exhibit the same alteration in the expression of IL-1RII, a key protector against tumorigenic effects of IL-1. Our findings highlight a common signature between endometrioid ovarian cancer and implants of endometriosis, which needs to be fully explored.

© 2010 The Authors. Journal compilation © 2010 Japan Society of Obstetrics and Gynecology.

Int J Surg Pathol. 2010 Nov 17. [Epub ahead of print]

Colonization of Intestinal Endometriosis by Benign Colonic Mucosa: A Pattern Potentially Misdiagnosed as Invasive Mucinous Carcinoma.

Tipps AM, Weidner N.

University of California.

Endometriosis is well known for creating diagnostic pitfalls for pathologists. It may produce masses mimicking neoplasms or cause diagnostic quandaries, particularly when the patient age, location, and/or epithelial appearance are atypical. This study reports a patient with endometriosis causing rectal bleeding and involving the cecum. It produced a mass clinically considered appendiceal. The endometriosis was focally lined by intestinal epithelium including Paneth cells. In the deep endometriotic glands embedded within intestinal wall, direct fusion of the intestinal and the endometrial epithelium-the benign intestinal epithelium apparently colonizing the endometriotic foci-was found. The mass effect, plus deep-seated intestinal epithelium, closely mimicked invasive well-differentiated mucinous carcinoma. This is yet another peculiar presentation of endometriosis with potential for misinterpretation as a more serious condition, specifically well-differentiated mucinous carcinoma of the cecum or appendix.

Fertil Steril. 2010 Nov 13. [Epub ahead of print]

Expression of oct-4 and c-kit antigens in endometriosis.

Pacchiarotti A, Caserta D, Sbracia M, Moscarini M.

University of Rome “Sapienza,” Rome, Italy.

The objective of this study was to test the expression of the oct-4 and c-kit, both markers of stem cells, in the ectopic endometrial tissue of endometriotic lesions of women with severe endometriosis. Our findings show that ectopic epithelial cells express oct-4 and c-kit and this suggests that the ectopic endometrium in endometriosis has a stem cell origin and could explain the possible progression to ovarian cancer.

Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Mol Cell Endocrinol. 2010 Nov 13. [Epub ahead of print]

Steroidogenic factor-1 (SF-1, NR5A1) and human disease.

Ferraz-de-Souza B, Lin L, Achermann JC.

Developmental Endocrinology Research Group, Clinical & Molecular Genetics Unit, UCL Institute of Child Health, University College London, London WC1N 1EH, United Kingdom.

Steroidogenic factor-1 (SF-1, Ad4BP, encoded by NR5A1) is a key regulator of adrenal and reproductive development and function. Based upon the features found in Nr5a1 null mice, initial attempts to identify SF-1 changes in humans focused on those rare individuals with primary adrenal failure, a 46,XY karyotype, complete gonadal dysgenesis and Müllerian structures. Although alterations affecting DNA-binding of SF-1 were found in two such cases, disruption of SF-1 is not commonly found in patients with adrenal failure. In contrast, it is emerging that variations in SF-1 can be found in association with a range of human reproductive phenotypes such as 46,XY disorders of sex development (DSD), hypospadias, anorchia, male factor infertility, or primary ovarian insufficiency in women. Overexpression or overactivity of SF-1 is also reported in some adrenal tumors or endometriosis. Therefore, the clinical spectrum of phenotypes associated with variations in SF-1 is expanding and the importance of this nuclear receptor in human endocrine disease is now firmly established.

Drugs. 2010 Nov 12;70(16):2073-88. doi: 10.2165/11206320-000000000-00000.

Dienogest: a review of its use in the treatment of endometriosis.

McCormack PL.

Adis, a Wolters Kluwer Business, Auckland, New Zealand. demail@adis.co.nz

Dienogest (Visanne®) is a synthetic oral progestogen with unique pharmacological properties that is indicated at a dosage of 2 mg/day for the treatment of endometriosis. It is generally highly selective for the progesterone receptor and displays strong progestational effects and moderate antigonadotrophic effects, but no androgenic, glucocorticoid or mineralocorticoid activity. Dienogest has moderate affinity for progesterone receptors (10% that of progesterone) and at a dosage of 2 mg/day only moderately suppresses estradiol levels. It has high oral bioavailability and a half-life suitable for once-daily administration. In randomized clinical trials, oral dienogest was significantly more effective than placebo in reducing pelvic pain in patients with confirmed endometriosis. In trials comparing oral dienogest for 16 or 24 weeks with gonadotropin-releasing hormone (GnRH) agonists commonly used in the treatment of endometriosis, dienogest was noninferior to depot leuprorelin in reducing pelvic pain and was not significantly different from intranasal buserelin and depot triptorelin in improving combined symptoms/signs scores or revised American Fertility Society (rAFS) staging scores, respectively. Improvements were also noted in some measures of health-related quality of life. The efficacy of dienogest was sustained during long-term treatment for more than 1 year. Dienogest was generally well tolerated and was not considered to be associated with clinically relevant androgenic effects. It appeared to have fewer hypoestrogenic effects than the GnRH agonists. Dienogest was associated with a high incidence of abnormal menstrual bleeding patterns, although this was generally well tolerated by patients, with few discontinuing therapy, and the bleeding intensity and frequency decreased over time. Therefore, oral dienogest offers an effective, generally well tolerated therapeutic option for the long-term treatment of endometriosis.

Eur J Obstet Gynecol Reprod Biol. 2010 Nov 12. [Epub ahead of print]

The value of serological markers in the diagnosis and prognosis of endometriosis: a prospective case-control study.

Socolov R, Butureanu S, Angioni S, Sindilar A, Boiculese L, Cozma L, Socolov D.

University of Medicine Gr. T. Popa Iasi, Romania.

OBJECTIVE: We analyzed selected well-known and less well-known serum markers that have been proposed for diagnosis and severity assessment of endometriosis, in a case-control study.

STUDY DESIGN: This prospective study was carried out in a Clinical Department of Gynecology in Iasi, Romania. Study participants included endometriosis patients, and controls in whom laparoscopy had excluded endometriosis. Each case and control was investigated for serum levels of CA125, TNF, IL-1, IL-6 and IL-8. The data were correlated with clinical symptoms and revised American Fertility Society (rAFS) score and stage, and interpreted by Mann-Whitney U-test and ANOVA regression analysis.

RESULTS: Over the course of 1 year, 24 cases of endometriosis and 24 controls of matched age were selected. The rAFS stages were: stage I, 12.5%; stage II, 16.7%; stage III, 58.3%; and stage IV, 12.5%. CA125 levels were over the cut-off of 35IU/l in 54% of patients (versus 8% of controls), averaging 67.5 (CI95: ±17.5). The sensitivity and specificity were 54% and 91%, respectively, with a p value of <0.001 (statistically significant). For IL-6, 71% of cases and 87% of controls were above the cut-off of 2pg/ml, with an average of 11.83±7. The sensitivity and specificity were 71% and 12%, respectively, but the difference was not statistically significant, p=0.071. Other tested serum markers had no discrimination value. A correlation with severity of endometriosis was seen for CA125 (p=0.03) but not for IL-6, by ANOVA.

CONCLUSION: CA125 correlated with endometriosis screening and severity, indicating its superiority as a marker for further, larger studies.

Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Arch Gynecol Obstet. 2010 Nov 11. [Epub ahead of print]

Highly elevated serum CA-125 levels in patients with non-malignant gynecological diseases.

He RH, Yao WM, Wu LY, Mao YY.

Department of Obstetrics and Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, Zhejiang, People’s Republic of China.

PURPOSES: To identify patients with highly elevated serum CA-125 levels and analyze their clinical characteristics.

METHODS: Patients with non-malignant gynecologic disease (NMGDs, n = 41), in whom serum CA-125 levels were over 1,000 IU/ml were retrospectively enrolled in the study. Seventy-one patients with epithelial ovarian cancer (EOC), in whom, serum CA-125 levels were over 1,000 IU/ml were included as the comparison group. Clinical parameters were compared between the two groups.

RESULTS: In NMGDs group, 43.90% of the patients had endometriosis. The median of serum CA-125 level in NMGDs was much lower than that of EOC subjects (P < 0.001). Compared to EOC group, the patients in NMGDs group were much younger (P < 0.001) and had fewer histories of pelvic masses (P < 0.001) but had more clinical complaints such as acute abdominal symptoms (P < 0.001) and/or abnormal vaginal bleeding (P = 0.022). Clinical progresses of these two groups were correlated with changes of serum CA-125 levels by follow-up for up to 386 days.

CONCLUSIONS: High levels of serum CA-125 were found not only in the EOC, but also in some NMGDs, especially in the reproductive patients with complaints of acute abdomen symptoms or abnormal vaginal bleeding.

Hum Reprod. 2010 Nov 11. [Epub ahead of print]

‘Waiting for Godot’: a commonsense approach to the medical treatment of endometriosis.

Vercellini P, Crosignani P, Somigliana E, Viganò P, Frattaruolo MP, Fedele L.

Department of Obstetrics and Gynaecology, Istituto ‘Luigi Mangiagalli’, University of Milan, Milan, Italy.

Conservative surgical treatment for symptomatic endometriosis is frequently associated with only partial relief of pelvic pain or its recurrence. Therefore, medical therapy constitutes an important alternative or complement to surgery. However, no available compound is cytoreductive, and suppression instead of elimination of implants is the only realistic objective of pharmacological intervention. Because this implies prolonged periods of treatments, only medications with a favourable safety/tolerability/efficacy/cost profile should be chosen. In the past few years, innumerable new drugs for endometriosis, which would interfere with several hypothesized pathogenic mechanisms, have been studied and their use foreseen. However, robust evidence of in vivo safety and efficacy is lacking and, at the moment, the principal modality to interfere with endometriosis metabolism is still hormonal manipulation. Regrettably, in spite of consistent demonstration of a major effect on pain even in patients with deeply infiltrating lesions, progestins are underestimated and dismissed in favour of more scientifically fashionable and up-to-the-minute alternatives. Moreover, oral contraceptives (OCs) dramatically reduce the rate of post-operative endometrioma recurrence and should now be considered an essential part of long-term therapeutic strategies in order to limit further damage to future fertility. Finally, women who have used OC for prolonged periods will be protected from an increased risk of endometriosis-associated ovarian cancer. To avoid the several subtle modalities for distorting facts and orientating opinions in favour of specific compounds, progestins and monophasic OC used continuously are here proposed as the reference comparator in all future randomized controlled trials on medical treatment for endometriosis.

Am J Obstet Gynecol. 2010 Nov 10. [Epub ahead of print]

Prognostic analysis of ovarian cancer associated with endometriosis.

Kumar S, Munkarah A, Arabi H, Bandyopadhyay S, Semaan A, Hayek K, Garg G, Morris R, Ali-Fehmi R.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI.

OBJECTIVE: The objective of the study was to evaluate the prognosis of ovarian cancer arising in endometriosis.

STUDY DESIGN: We retrospectively compared 42 cases of endometriosis-associated ovarian cancer (EAOC) with 184 cases of ovarian carcinoma without endometriosis (OC).

RESULTS: The median age in the EAOC group was 52 vs 59 years in OC (P < .05). In comparison with OC, the EAOC patients were more likely to have low-grade (21% vs 8%; P = .04) and early-stage tumors (International Federation of Gynecology and Obstetrics I and II combined) (49% vs 24%; P = .002). Clear cell (21% vs 2%) and endometrioid (14% vs 3%) tumors were more frequent in EAOC, whereas mucinous tumors were more prevalent in OC (P = .001). The median survival (199 vs 62 months) and the 5 year survival (62% vs 51%) were better for EAOC when compared with OC (P = .038). After controlling for age, stage, grade, and treatment, association with endometriosis was not an independent predictor of better survival in ovarian cancer.

CONCLUSION: As such, EAOC has a much better survival rate than OC. This could be explained by the higher prevalence of early-stage and low-grade tumors in EAOC when compared with OC.

Copyright © 2010 Mosby, Inc. All rights reserved.

Cochrane Database Syst Rev. 2010 Nov 10;11:CD008571.

Interventions for women with endometrioma prior to assisted reproductive technology.

Benschop L, Farquhar C, van der Poel N, Heineman MJ.

Department of Obstetrics & Gynaecology Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands.

BACKGROUND: Endometriomata are cysts of endometriosis in the ovaries. As artificial reproductive technology (ART) cycles involve oocyte pickup from the ovaries, endometriomata may interfere with the outcome of ART.

OBJECTIVES: To determine the effectiveness and safety of surgery, medical treatment, combination therapy or no treatment for improving reproductive outcomes among women with endometriomata, prior to undergoing ART cycles.

SEARCH STRATEGY: The review authors searched: Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials, CENTRAL (The Cochrane Library), EMBASE, MEDLINE, PubMed, PsycINFO, CINAHL, DARE, trial registers for ongoing and registered trials, citation indexes, conference abstracts on the ISI Web of Knowledge, Clinical Study Results, OpenSIGLE (July 2010) and handsearched Fertility and Sterility (2008 to 2010).

SELECTION CRITERIA: Randomised controlled trials of any medical, surgical or combination therapy or expectant management for endometriomata prior to ART.

DATA COLLECTION AND ANALYSIS: The trials were independently identified and assessed for risk of bias by two authors. The authors of the trials that were potentially eligible for inclusion were contacted for additional information. Outcomes were expressed as Peto odds ratios and mean differences (MD).

MAIN RESULTS: Eleven trials were identified of which seven were excluded and four with 312 participants were included.No trial reported live birth outcomes. One trial compared gonadotropin-releasing hormone (GnRH) agonist with GnRH antagonist. There was no evidence of a difference for clinical pregnancy rate (CPR), however the number of mature oocytes retrieved (NMOR) was greater with GnRH agonists (MD -1.60, 95% CI -2.44 to -0.76) and the ovarian response was increased (estradiol (E2) levels on day of human chorionic gonadotropin (hCG) injection) (MD -456.30, 95% CI -896.06 to -16.54).Surgery (aspiration or cystectomy) versus expectant management (EM) showed no evidence of a benefit for clinical pregnancy with either technique. Aspiration was associated with greater NMOR (MD 0.50, 95% CI 0.02 to 0.98) and increased ovarian response (E2 levels on day of hCG injection) (MD 685.3, 95% CI 464.50 to 906.10) compared to EM.Cystectomy was associated with a decreased ovarian response to controlled ovarian hyperstimulation (COH) (MD -510.00, 95% CI -676.62 to -343.38); no evidence of an effect on the NMOR compared to EM. Aspiration versus cystectomy showed no evidence of a difference in CPR or the NMOR.

AUTHORS’ CONCLUSIONS: There was no evidence of an effect on reproductive outcomes in any of the four included trials. Further RCTs of management of endometrioma in women undergoing ART are required.

Fertil Steril. 2010 Nov 10. [Epub ahead of print]

Questioning patients about their adolescent history can identify markers associated with deep infiltrating endometriosis.

Chapron C, Lafay-Pillet MC, Monceau E, Borghese B, Ngô C, Souza C, de Ziegler D.

Université Paris Descartes, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Universitaire Ouest, Centre Hospitalier Universitaire Cochin Saint Vincent de Paul, Service de Gynécologie Obstétrique II and Reproductive Medicine, Paris, France; Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, Unité de Recherche U1016, Paris, France.

OBJECTIVE: To investigate whether the clinical history, particularly of the adolescence period, contains markers of deeply infiltrating endometriosis (DIE).

DESIGN: Cross-sectional study.

SETTING: Universitary tertiary referral center.

PATIENT(S): Two hundred twenty-nine patients operated on for endometriosis. Endometriotic lesions were histologically confirmed as non-DIE (superficial peritoneal endometriosis and/or ovarian endometriomas) (n = 131) or DIE (n = 98).

INTERVENTION(S): Surgical excision of endometriotic lesions with pathological analysis of each specimens.

MAIN OUTCOME MEASURE(S): Epidemiological data, pelvic pain scores, family history of endometriosis, absenteeism from school during menstruation, oral contraceptive (OC) pill use.

RESULT(S): Patients with DIE had significantly more positive family history of endometriosis (odds ratio [OR] = 3.2; 95% confidence interval [CI]: 1.2-8.8) and more absenteeism from school during menstruation (OR = 1.7; 95% CI: 1-3). The OC pill use for treating severe primary dysmenorrhea was more frequent in patients with DIE (OR = 4.5; 95% CI: 1.9-10.4). Duration of OC pill use for severe primary dysmenorrhea was longer in patients with DIE (8.4 ± 4.7 years vs. 5.1 ± 3.8 years). There was a higher incidence of OC pill use for severe primary dysmenorrhea before 18 years of age in patients with DIE (OR = 4.2; 95% CI: 1.8-10.0).

CONCLUSION(S): The knowledge of adolescent period history can identify markers that are associated with DIE in patients undergoing surgery for endometriosis.

Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Reprod Sci. 2010 Nov 9. [Epub ahead of print]

Molecular Evidence for Differences in Endometrium in Severe Versus Mild Endometriosis.

Aghajanova L, Giudice LC.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco (UCSF), San Francisco, CA, USA.

Women with stage III/IV versus stage I/II endometriosis have lower implantation and pregnancy rates in natural and assisted reproduction cycles. To elucidate potential molecular mechanisms underlying these clinical observations, herein we investigated the transcriptome of eutopic endometrium across the menstrual cycle in the setting of severe versus mild endometriosis. Proliferative (PE), early secretory (ESE), and mid-secretory (MSE) endometrial tissues were obtained from 63 participants with endometriosis (19 mild and 44 severe). Purified RNA was subjected to microarray analysis using the Gene 1.0 ST Affymetrix platform. Data were analyzed with GeneSpring and Ingenuity Pathway Analysis and subsequently validated. Comparison of differentially regulated genes, analyzed by cycle phase, revealed dysregulation of progesterone and/or cyclic adenosine monophosphate (cAMP)-regulated genes and genes related to thyroid hormone action and metabolism. Also, members of the epidermal growth factor receptor (EGFR) signaling pathway were observed, with the greatest upregulation of EGFR in severe versus mild disease during the early secretory phase. The extracellular matrix proteoglycan versican (VCAN), which regulates cell proliferation and apoptosis, was the most highly expressed gene in severe versus mild disease. Upregulation of microRNA 21 (MIR21) and DICER1 transcripts suggests roles for microRNAs (miRNAs) in the pathogenesis of severe versus mild endometriosis, potentially through regulation of gene silencing and epigenetic mechanisms. These observed differences in transcriptomic signatures and signaling pathways may result in poorly programmed endometrium during the cycle, contributing to lower implantation and pregnancy rates in women with severe versus mild endometriosis.

Fertil Steril. 2010 Nov 3. [Epub ahead of print]

Effects of hyperprolactinemia treatment with the dopamine agonist quinagolide on endometriotic lesions in patients with endometriosis-associated hyperprolactinemia.

Gómez R, Abad A, Delgado F, Tamarit S, Simón C, Pellicer A.

Instituto Universitario InstitutoValenciano de Infertilidad, Valencia University School of Medicine and INCLIVA, Valencia, Spain.

OBJECTIVE: To assess whether dopamine receptor 2 agonists reduced the size of peritoneal lesions in women with endometriosis and elucidate whether affectation of vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2)-dependent angiogenesis was mediating the observed effects.

SETTING: University hospital and a university-affiliated private IVF research center.

DESIGN: Proof-of-concept study.

PATIENT(S): Hyperprolactinemic patients (n = 9) with endometriosis requiring a first surgical intervention (L1) and benefiting from a second-look laparoscopy (L2) were evaluated.

INTERVENTION(S): During L1, four to six peritoneal red lesions were identified. One-half of the lesions were removed and the remaining one-half were labeled with silk knot sutures. After L1, quinagolide was administered in a titrated manner (25-75 μg/d) for 18-20 weeks. During L2, the remaining lesions were surgically excised.

MAIN OUTCOME MEASURE(S): Both L1 and L2 were video recorded to compare the effects of quinagolide treatment on lesion size. Lesions removed at L1 and L2 were compared by means of: 1) histologic analysis; 2) immunohistochemical quantitative analysis of angiogenesis; and 3) quantitative fluorescence polymerase chain reaction array analysis of 84 chemokines and pro-/antiangiogenic molecules.

RESULT(S): Quinagolide induced a 69.5% reduction in the size of the lesions, with 35% vanishing completely. Histologic analysis showed tissue degeneration, which was supported by down-regulation of VEGF/VEGFR2, three proangiogenic cytokines (CCL2, RUNX1, and AGGF1) and plasminogen activator inhibitor (PAI) 1, a potent inhibitor of fibrinolysis in the L2 lesions.

CONCLUSION(S): By interfering with angiogenesis, enhancing fibrinolysis, and reducing inflammation, quinagolide reduces or eliminates peritoneal endometriotic lesions in women with endometriosis.

Copyright © 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Acta Obstet Gynecol Scand. 2010 Nov;89(11):1372-3.

Adenomyosis to uterine transplantation.

Geirsson RT.

Acta Obstet Gynecol Scand. 2010 Nov;89(11):1374-84. Epub 2010 Oct 8.

Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy.

Champaneria R, Abedin P, Daniels J, Balogun M, Khan KS.

University of Birmingham, Birmingham Women’s Hospital, UK. r.champaneria@bham.ac.uk

BACKGROUND: Adenomyosis is a common condition that causes substantial morbidity. Until recently, the reference standard for a definitive diagnosis was histology of hysterectomy specimens. Ultrasound and magnetic resonance imaging (MRI) may allow accurate non-invasive diagnosis.

OBJECTIVE: To compare the diagnostic accuracy of these techniques.

DESIGN: Systematic review with meta-analysis.

POPULATION: Women who had ultrasound and/or MRI, and whose results were compared with a reference standard.

METHODS: Electronic searches were conducted in literature databases from database inception to 2010. The reference lists of known relevant articles were searched for further articles. Selected studies reported data on ultrasound and/or MRI with histological confirmation of diagnosis. Two reviewers independently selected articles without language restrictions, and extracted data in the form of 2 × 2 tables. We computed sensitivity and specificity for individual studies and pooled these results in a meta-analysis. We also performed meta-regression to examine how the index tests compared on diagnostic accuracy.

RESULTS: Twenty-three articles (involving 2,312 women) satisfied the inclusion criteria. Transvaginal ultrasound had a pooled sensitivity of 72% (95% CI 65-79%), specificity of 81% (95% CI 77-85%), positive likelihood ratio of 3.7 (95% CI 2.1-6.4) and negative likelihood ratio of 0.3 (95% CI 0.1-0.5). MRI had a pooled sensitivity of 77% (95% CI 67-85%), specificity of 89% (95% CI 84-92%), positive likelihood ratio of 6.5 (95% CI 4.5-9.3), and negative likelihood ratio of 0.2 (95% CI 0.1-0.4). The results show that a correct diagnosis was obtained more often with MRI.

CONCLUSION: Transvaginal ultrasound and MRI show high levels of accuracy for the non-invasive diagnosis of adenomyosis.

Acta Obstet Gynecol Scand. 2010 Nov;89(11):1424-31. Epub 2010 Aug 30.

Unilateral renal agenesis and female genital tract pathologies.

Acién P, Acién M.

University Hospital of San Juan, Alicante, Spain. acien@umh.es

OBJECTIVES: To analyze the gynecological pathologies and extragenital anomalies associated with unilateral renal agenesis (URA) and the possible origin of these congenital anomalies.

DESIGN: Retrospective case-control study.

SETTING: University Hospital.

POPULATION: This study included 276 women with genitourinary malformations who had undergone hysterosalpingography (and/or laparoscopy) and pyelography with images available for review.

METHODS: There were 60 cases of women diagnosed with genital malformations and congenital URA and 216 control cases of women with genital tract malformations and both kidneys present. All cases were categorized according to an embryological-clinical classification and the type of Müllerian malformation (American Society for Reproductive Medicine (ASRM) classification) and then compared by type for the presence of gynecological and extragenital pathologies.

MAIN OUTCOME MEASURES: Genital malformations, endometriosis, leiomyomas and skeletal anomalies.

RESULTS: URA was generally associated with either agenesis of all of the derivatives of the urogenital ridge on the same side of the body, which were usually found on the left, or distal mesonephric anomalies such as a double uterus with a blind hemivagina or unilateral cervico-vaginal atresia, which were most frequently on the right. The uterine malformations that were most commonly seen in women with renal agenesis were bicornis-bicollis, didelphys and unicornuate uteri. Women with bicornuate or didelphys uteri and renal agenesis had more gynecological pathologies, such as endometriosis, than those with both kidneys present.

CONCLUSIONS: URA and major uterine malformations are frequently related, and individuals with bicornuate or didelphys uteri have endometriosis more often than those without renal agenesis. Those malformations that seem to be caused by the absence or anomaly of a mesonephric duct lead to renal agenesis, ipsilateral vaginal anomalies (blind or atretic hemivagina) and failure of the induction function of the Wolffian ducts on the Müllerian ducts, causing uterine malformations.

Am J Pathol. 2010 Nov;177(5):2495-508.

Olfactomedin-4 regulation by estrogen in the human endometrium requires epidermal growth factor signaling.

Dassen H, Punyadeera C, Delvoux B, Schulkens I, Marchetti C, Kamps R, Klomp J, Dijcks F, de Goeij A, D’Hooghe T, Kyama C, Ederveen A, Dunselman G, Groothuis P, Romano A.

GROW–School for Oncology and Developmental Biology, Department of Pathology, Maastricht University and Medical Centre, 6202 AZ, Maastricht, The Netherlands.

Olfactomedin-4 (OLFM-4) is an extracellular matrix protein that is highly expressed in human endometrium. We have examined the regulation and function of OLFM-4 in normal endometrium and in cases of endometriosis and endometrial cancer. OLFM-4 expression levels are highest in proliferative-phase endometrium, and 17β-estradiol up-regulates OLFM-4 mRNA in endometrial explant cultures. Using the luciferase reporter under control of the OLFM-4 promoter, it was shown that both 17β-estradiol and OH-tamoxifen induce luciferase activity, and epidermal growth factor receptor-1 is required for this estrogenic response. In turn, EGF activates the OLFM-4 promoter, and estrogen receptor-α is needed for the complete EGF response. The cellular functions of OLFM-4 were examined by its expression in OLFM-4-negative HEK-293 cells, which resulted in decreased vimentin expression and cell adherence as well as increased apoptosis resistance. In cases of endometriosis and endometrial cancer, OLFM-4 expression correlated with the presence of epidermal growth factor receptor-1 and estrogen receptor-α (or estrogen signaling). An increase of OLFM-4 mRNA was observed in the endometrium of endometriosis patients. No change in OLFM-4 expression levels were observed in patients with endometrial cancer relative with controls. In conclusion, cross-talk between estrogen and EGF signaling regulates OLFM-4 expression. The role of OLFM-4 in endometrial tissue remodeling before the secretory phase and during the predisposition and early events in endometriosis can be postulated but requires additional investigation.

Am J Reprod Immunol. 2010 Nov;64(5):333-8. doi: 10.1111/j.1600-0897.2010.00882.x.

Association of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala polymorphism with advanced-stage endometriosis.

Hwang KR, Choi YM, Kim JM, Lee GH, Kim JJ, Chae SJ, Moon SY.

Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Korea.

PROBLEM: To investigate whether the peroxisome proliferator-activated receptor (PPAR)-γ2 Pro12Ala polymorphism is associated with a risk of advanced-stage endometriosis in a Korean population.

METHODS OF STUDY:  Case-control  study in a collective of 446 patients and 427 controls. The Pro12Ala polymorphism of PPAR-γ2 gene was genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.

RESULTS: The distribution of the PPAR-γ2 Pro12Ala polymorphism was different between the advanced-stage endometriosis group and the control group (non-CC rates were 5.2% for patients with advanced endometriosis and 10.1% for the control group, respectively, P = 0.006). The frequency for the Ala-12 allele variant was significantly lower in patients with advanced stage of endometriosis (2.7%) than in the control group (5.3%) (P = 0.006).

CONCLUSION: These findings suggest that the PPAR-γ2 Pro12Ala polymorphism is associated with advanced-stage endometriosis in the Korean population. Unlike results from other studies reported so far, the Ala-12 allele may have protective effects against advanced-stage endometriosis in the Korean population.

© 2010 John Wiley & Sons A/S.

Am J Reprod Immunol. 2010 Nov;64(5):318-23. doi: 10.1111/j.1600-0897.2010.00840.x.

Resistin concentration is increased in the peritoneal fluid of women with endometriosis.

Yi KW, Shin JH, Park HT, Kim T, Kim SH, Hur JY.

Department of Obstetrics and Gynecology, Korea University, Seoul, Korea.

PROBLEM: The aim of this study was to investigate the concentration of resistin and adiponectin in the peritoneal fluid (PF) of patients with endometriosis.

METHOD OF STUDY: PF sampling was obtained from women with (n = 48) and without endometriosis (n = 36), and the anthropometric indices of the patients were measured. Resistin and adiponectin concentrations in the PF were determined using the enzyme-linked immunosorbent assay.

RESULTS: The mean concentration of PF resistin was significantly higher in women with endometriosis compared to the controls. PF resistin concentrations were not associated with any of the anthropometric indices. The PF adiponectin did not differ between the two groups, but showed a significant association with the weight, body mass index, and hip circumference. After adjusting for these factors, PF adiponectin expression was not associated with endometriosis.

CONCLUSION: The findings of this study suggest a potent role for resistin in endometriosis. Further studies are needed to elucidate the biological implications of resistin in endometriosis.

© 2010 John Wiley & Sons A/S.

Amino Acids. 2010 Nov;39(5):1147-60. Epub 2010 Mar 31.

Structural elucidation of Leuprolide and its analogues in solution: insight into their bioactive conformation.

Laimou DK, Katsara M, Matsoukas MT, Apostolopoulos V, Troganis AN, Tselios TV.

Department of Chemistry, University of Patras, Patras, 26500, Greece.

Leuprolide [DLeu6, NHEt10]GnRH, a potent gonadotropin-releasing hormone (GnRH) agonist, is used in a wide variety of hormone-related diseases like cancer and endometriosis. In this report, the conformational behaviour of Leuprolide and its linear synthetic analogues, namely [Tyr5(OMe), DLeu6, Aze9, NHEt10]GnRH (1) and [Tyr5(OMe), DLeu6, NHEt10]GnRH (2) have been studied in DMSO and H2O solutions by means of 2D nuclear magnetic resonance (NMR) experiments and detailed molecular dynamics (MD) simulations. The aim was to identify the conformational requirements of GnRH analogues for agonistic activity. This approach is of value as no crystallographic data are available for the GnRH receptor (G protein-coupled receptor, GPCR). The NOE data indicate the existence of a β-turn type I in the 2-5 segments of Leuprolide and its linear analogues in the case of using DMSO-d6 as solvent, whereas a β-turn type II in the 3-6 segments is indicated using D2O as solvent. The final structures fulfil the conformational requirements that are known, in the literature, to play a significant role in receptor recognition and activation. Finally, the linear analogues (1) and (2) are biologically active when tested against the human breast cancer cell line, MCF-7.

Arch Gynecol Obstet. 2010 Nov;282(5):507-14. Epub 2009 Dec 15.

Effect and safety of high-dose dienogest (20 mg/day) in the treatment of women with endometriosis.

Schindler AE, Henkel A, Moore C, Oettel M.

Institute for Medical Research and Education, 45122 Essen, Germany. adolf.schindler@uni-due.de

PURPOSE: Hormonal treatment of endometriosis is often continued for long periods and has the potential to affect many essential metabolic processes. The current study aimed to determine the effects and safety of high-dose dienogest as a medical endometriosis therapy.

METHODS: The effects and safety of high-dose dienogest, 20-30 mg/day for 24 weeks, were examined in 21 women aged 18-52 years with laparoscopically and histologically proven endometriosis stage I-IV (according to revised American Society of Reproductive Medicine criteria). At baseline and week 24, sera were obtained and stored at -20°C prior to analysis.

RESULTS: The study showed no clinically significant effect of high-dose dienogest on thyroid or adrenal function, electrolyte balance or haematopoiesis. High-dose dienogest therapy also had no appreciable effects on glucose and lipid metabolism, liver enzymes or haemostasis. For instance, although dienogest mediated small increases in the haemostatic variables prothrombin fragment 1 + 2, antithrombin III and protein C, final levels (at week 24) remained within normal reference ranges for these parameters. The exception was the HDL-3 cholesterol concentration at week 24 (0.97 mmol/l), which increased beyond the normal range of 0.28-0.64 mmol/l.

CONCLUSIONS: This investigation yielded a unique dataset on the safety of high-dose dienogest in endometriosis stage I-IV. High-dose dienogest (20-30 mg/day) had little influence upon all the parameters measured. It is therefore likely that lower doses of dienogest would have similarly neutral safety effects: an important consideration in the use of dienogest for the treatment of endometriosis.

Biol Reprod. 2010 Nov;83(5):866-73. Epub 2010 Jun 23.

Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium: a novel molecular target for endometriosis therapy.

Novella-Maestre E, Carda C, Ruiz-Sauri A, Garcia-Velasco JA, Simon C, Pellicer A.

Unidad de Genetica, Hospital Universitario La Fe, Valencia, Spain. edurnenovella@yahoo.es

Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist (DA) cabergoline (Cb2) reduces angiogenesis and endometriotic lesions, hypothetically binding to the dopamine receptor type-2 (DRD2). To date, this has not been described in human endometrium and/or endometriotic lesions. Thus, we aimed to investigate the presence of DRD2 in said tissues. Endometrium fragments were implanted in nude mice treated with different doses of Cb2. Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions (respectively) of DRD2, VEGF, and VEGF receptor-2 (KDR). In addition, lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile. In experimental endometriosis, DRD2 was expressed at gene and protein levels in all three groups. VEGF gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls. KDR protein expression was significantly lower in experimental lesions treated with Cb2 than in controls. In eutopic endometria, there was a significant decrease in DRD2 expression and an increase in VEGF in women with mild and severe endometriosis with respect to healthy patients. In endometriosis, KDR expression was significantly higher in red than in white and black lesions. VEGF expression was significantly lower in black than in red lesions. DRD2 is present in the human eutopic and ectopic endometrium and is regulated by DA, which provides the rationale for pilot studies to explore its use in the treatment of endometriosis.

Colorectal Dis. 2010 Nov;12(11):1105-12. doi: 10.1111/j.1463-1318.2009.01993.x.

Laparoscopic excision of rectovaginal endometriosis: report of a prospective study and review of the literature.

Maytham GD, Dowson HM, Levy B, Kent A, Rockall TA.

Minimal Access Therapy Training Unit (MATTU), Post-Graduate Medical School, University of Surrey, Manor Park, Guildford, UK. gdmaytham@mac.com

AIM: The surgical management of rectovaginal endometriosis is challenging. We present our experience of the laparoscopic management of these difficult cases, together with a review of the current literature.

METHOD: A prospective database was established for all patients undergoing surgery for Deep Infiltrating Endometriosis (DIE) with rectovaginal and/or ureteric and bladder nodules. Outcomes analysed include operation performed, conversion and complication rates, and length of stay. These outcomes were compared with other laparoscopic rectal resections for alternative diagnoses recorded in the database and with outcomes seen in a literature review of studies on the surgical management of endometriosis.

RESULTS: Between April 2004 and November 2007, 54 patients underwent laparoscopic excision of rectovaginal endometriosis by a combined colorectal and gynaecological surgical team. Out of the 54 patients, 37% of patients underwent a rectal wall shave, 13% had a disc excision of the rectal wall, and 50% underwent segmental resection. There was a conversion rate of 4%, median duration of stay was 3 days, with 2% requiring transfusion. Major complications occurred in 7% of patients, with 4% requiring reoperation. Patients undergoing segmental resection for endometriosis had a higher complication rate than those having surgery for other diagnoses. There was an increased incidence of anastomotic stenosis, with histopathological results suggesting that the disease process might have contributed to this occurrence.

CONCLUSIONS: Laparoscopic resection of rectovaginal endometriosis may be associated with a higher incidence of complications than resections performed for other diagnoses.

© 2010 The Authors. Colorectal Disease © 2010 The Association of Coloproctology of Great Britain and Ireland.

Contraception. 2010 Nov;82(5):442-52. Epub 2010 Feb 1.

Mifepristone: where do we come from and where are we going? Clinical development over a quarter of a century.

Spitz IM.

Institute of Hormone Research and Ben Gurion University of the Negev, Jerusalem 92548, Israel. Irving@spitz.com

Administration of mifepristone followed by the prostaglandin, misoprostol, has been used successfully in the medical termination of pregnancy for over 25 years, and the method is registered in 35 countries. Single doses of mifepristone are also effective as an emergency postcoital contraceptive. Mifepristone administered for 3 months or longer to women with uterine leiomyomas, is associated with a reduction in pain and bleeding with improvement in quality of life and decrease in fibroid size. Mifepristone is also effective in decreasing pain in women with endometriosis. In both these conditions, serum estradiol levels are in the range of those in the early follicular phase. A daily dose of at least 2 mg mifepristone blocks ovulation. In contrast, weekly administration of 25 or 50 mg does not consistently block ovulation but has contraceptive potential by delaying endometrial development. Mifepristone in a dose of 200 mg, administered 48 h after the Luteinizing Hormone (LH) surge, also acts as a contraceptive, but this strategy is not practical for widespread use. Administration of mifepristone for 4-6 months or longer may lead to endometrial thickening. Endometrial histology reveals cystic glandular dilation together with admixed estrogen (mitotic) and progestin (secretory) epithelial effects. This histological pattern does not represent endometrial hyperplasia.

Copyright © 2010 Elsevier Inc. All rights reserved.

Contraception. 2010 Nov;82(5):396-403.

Non-contraceptive health benefits of intrauterine hormonal systems.

Fraser IS.

Department of Obstetrics, Gynaecology and Neonatology, Queen Elizabeth II Research Institute for Mothers and Infants, University of Sydney, NSW 2006, Australia. i_fraser@med.usyd.edu.au

Non-contraceptive health benefits are now recognized as an important aspect of the overall impact of all hormonal contraceptives. The levonorgestrel-releasing intrauterine systems (LNG IUS) are particularly effective at producing a number of health benefits for women using the LNG IUS as a contraceptive (reduced menstrual bleeding; reduced dysmenorrhea and the potential for prevention of a number of gynecological conditions in the longer term, such as iron-deficiency anemia, endometrial hyperplasia, uterine fibroids, acute episodes of pelvic inflammatory disease, endometriosis and perhaps others). The LNG IUS also has the potential to specifically treat a range of pre-existing gynecological conditions such as heavy menstrual bleeding due to a wide range of underlying causes, endometrial hyperplasia, uterine fibroids, adenomyosis, and endometriosis. These health benefits should be recognized as a key component in the decision-making process for individual women in choosing a specific type of hormonal or other contraceptive. Investment in research into the very substantial health benefits of hormonal contraceptives, such as the LNG IUS, has generally been ignored in comparison with the massive investment into understanding the often subtle or rare complications of hormonal contraceptive use. Both are important, but there is a real need to define more accurately those women who will benefit most from these health benefits.

DNA Cell Biol. 2010 Nov;29(11):663-7. Epub 2010 Jul 27.

Association of an interleukin-16 gene polymorphism with the risk and pain phenotype of endometriosis.

Gan XL, Lin YH, Zhang Y, Yu TH, Hu LN.

Department of Gynecology and Obstetrics, West China Secondary Hospital, Sichuan University, Chengdu, PR China.

Interleukin-16 (IL-16), a proinflammatory cytokine, plays a pivotal role in inflammatory diseases as well as in the pathogenesis of endometriosis. The aim of this study was to evaluate the association of IL-16 gene polymorphisms with the risk and clinical phenotypes of endometriosis in Chinese women. We analyzed rs4778889 T/C, rs11556218 T/G polymorphisms of the IL-16 gene in 230 patients with endometriosis and 203 controls in a Chinese population, using a polymerase chain reaction-high resolution melting analysis strategy and DNA sequencing methods. There was no significant difference in the genotype and allele frequencies of the rs11556218 T/G polymorphism between patients with endometriosis and controls (p>0.05). In contrast, the genotype and allele frequencies of the rs4778889 T/C polymorphism were statistically different between patients with endometriosis and controls, which resulted from a significantly increased proportion of TC heterozygote and CC homozygote carriers among patients with endometriosis (p=0.001 and 0.012, respectively); moreover, further subgroup analysis found that the genotype difference was more evident in patients with endometriosis who also experienced pain symptoms (p<0.001) than in patients without pain symptoms (p=0.625) when compared with controls. Our results suggest that the rs4778889 T/C polymorphism of the IL-16 gene may be associated with risk of endometriosis in the Chinese population, especially in patients with pain phenotype.

Endocrinology.

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