Am J Surg Pathol. 2008 Sep;32(9):1380-7.

Expression of PAX8 in nephrogenic adenoma and clear cell adenocarcinoma of the lower urinary tract: evidence of related histogenesis?

Tong GX, Weeden EM, Hamele-Bena D, Huan Y, Unger P, Memeo L, O’Toole K.

Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA. gt2125@columbia.edu

Recent evidence has showed that nephrogenic adenoma is a true “nephrogenic” lesion derived from the proliferation of exfoliated and implanted renal tubular cells in the urinary tract, a process that closely resembles the formation of endometriosis. This new concept has led to the identification of renal transcription factor PAX2 as a diagnostic marker for nephrogenic adenoma. PAX8 is another transcription factor structurally and functionally related to PAX2. Both are cell lineage restricted transcription factors expressed in normal and neoplastic tissues of related origin, including renal tubular cells in both fetal and adult kidneys. In this study, we investigated the expression of PAX8 in nephrogenic adenoma and its mimics. We report here that PAX8 was detected in all nephrogenic adenomas (N=35) and clear cell adenocarcinoma of the lower urinary tract (N=7), but not in prostate adenocarcinoma (N=100), adenocarcinoma (N=9), squamous cell carcinoma (N=5), or urothelial carcinoma (N=48) of the urinary bladder and its variants. PAX8 was neither detected in normal urothelium of the urinary bladder nor in prostate glands and stroma. PAX2 was also detected in 2 of the 7 clear cell adenocarcinomas of the lower urinary tract. We suggest that PAX8 is an additional marker for identifying nephrogenic adenoma. Expression of PAX8 or PAX2 in both nephrogenic adenoma and clear cell adenocarcinoma of the lower urinary tract may indicate a possible related tissue origin for these 2 lesions; both may be derived from proliferating renal tubular cells in the urinary tract. In addition, detection of PAX8 or PAX2 in clear cell adenocarcinoma of the lower urinary tract is helpful in differentiating it from urothelial carcinoma and its variants and adenocarcinomas of the urinary bladder or of the prostate.

Obstet Gynecol. 2008 Aug;112(2 Pt 2):475-7.

Clear cell adenocarcinoma arising in endometriosis of a previous episiotomy site.

Kwon YS, Nam JH, Choi G.

Department of Obstetrics and Gynecology, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea.

BACKGROUND: Malignant transformation of endometriosis in an episiotomy site is rare. CASE: A 42-year-old woman presented with a palpable mass, 2.5 cm in size, just inside the posterior commissure of the vagina, at the site of a previous episiotomy for a vaginal delivery. Three years previously, an endometriotic cyst had been excised at the same site, and the patient had been treated with a gonadotropin-releasing hormone analogue for 6 months. Biopsy revealed a clear cell adenocarcinoma arising in endometriosis. The patient underwent radical surgery alone without adjuvant therapy. At 10-month follow-up, there was no evidence of recurrence. CONCLUSION: Patients who experience a recurrence of extragonadal endometriosis after prior therapy should be monitored carefully for malignant degeneration.

Obstet Gynecol. 2008 Aug;112(2 Pt 2):448-50.

Intraperitoneal India ink deposits appearing as endometriosis in a patient with chronic pelvic pain.

Algoe KK, Chen H, Schned AR, Whiteside JL.

Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Departments of Obstetrics and Gynecology and Pathology, Lebanon, NH 03756, USA. kristin.k.algoe@hitchcock.org

BACKGROUND: Visualization and biopsy of suspicious peritoneum can confirm endometriosis. Endoscopic India ink tattooing can lead to peritoneum that visually mimics endometriosis. CASE: A woman with chronic pelvic pain and a history of treated endometriosis underwent diagnostic laparoscopy. Previously, a small bowel endoscopy had been performed to evaluate the pain. At laparoscopy, black peritoneal lesions were seen and biopsied due to concern for endometriosis. Pathology concluded the lesions to be carbon-based ink. Investigation revealed that tattoos placed during the small bowel endoscopy used India ink. CONCLUSION: Endoscopic India ink tattooing used to demarcate an area of bowel for later identification can stain peritoneal surfaces and mimic endometriotic implants.

Obstet Gynecol. 2008 Aug;112(2 Pt 1):405-7.

ACOG Committee Opinion. Aromatase inhibitors in gynecologic practice.

American College of Obstetricians and Gynecologists.

 

J Comput Assist Tomogr. 2008 Jul-Aug;32(4):555-8.

Decidualized endometrioma during pregnancy: recognizing an imaging mimic of ovarian malignancy.

Poder L, Coakley FV, Rabban JT, Goldstein RB, Aziz S, Chen LM.

Department of Radiology, University of California San Francisco, San Francisco, CA 94143-0628, USA.

OBJECTIVE: To present the ultrasound and magnetic resonance imaging findings that may allow for a prospective diagnosis and expectant management of decidualized endometriomas because the rare occurrence of decidualization in the ectopic endometrial stroma of an endometrioma during pregnancy can mimic ovarian cancer at imaging. CASE REPORT: Smooth lobulated mural nodules with prominent internal vascularity were noted in an apparent right ovarian endometrioma on serial ultrasound studies in a 34-year-old woman at 12, 21, 27, and 30 weeks of gestation. Magnetic resonance imaging demonstrated the nodules to be strikingly similar in intensity and texture to the decidualized endometrium in the uterus on T2-weighted sequences. A provisional diagnosis of decidualized endometrioma allowed for expectant management with immediate postpartum resection and confirmation of the diagnosis. CONCLUSIONS: Decidualized endometrioma can mimic ovarian malignancy during pregnancy, but a prospective diagnosis may be possible when solid smoothly lobulated nodules with prominent internal vascularity within an endometrioma are seen from early in pregnancy, and the nodules demonstrate marked similarity in signal intensity and texture with the decidualized endometrium in the uterus at magnetic resonance imaging.

Hum Reprod. 2008 Nov;23(11):2452-7. Epub 2008 Jul 29.

Diagnostic value of transvaginal ‘tenderness-guided’ ultrasonography for the prediction of location of deep endometriosis.

Guerriero S, Ajossa S, Gerada M, Virgilio B, Angioni S, Melis GB.

Department of Obstetrics and Gynaecology, University of Cagliari, Ospedale San Giovanni di Dio, Cagliari, Italy. gineca.sguerriero@tiscali.it

BACKGROUND: The aim was to evaluate the diagnostic accuracy of transvaginal tenderness-guided ultrasonography in the identification of location of deep endometriosis. METHODS: Consecutive women scheduled for surgery in our Department for clinically suspected endometriosis were included in this prospective study. All women underwent modified transvaginal ultrasonography using a stand-off in the week before surgery, which also evaluated the painful sites evocated by a gentle pressure of the probe. Five locations of deep endometriosis were considered: vaginal walls, rectovaginal septum, rectosigmoid involvement, uterosacral ligaments and anterior compartment (anterior pouch and/or bladder). Sensitivity, specificity and likelihood ratios (LR+/-) were calculated with 95% confidence intervals (CIs). RESULTS: We included 88 women; surgery associated with histopathological evaluation revealed deep endometriosis in different pelvic locations in 72 patients. With respect to the vaginal walls, transvaginal ultrasonography had a sensitivity of 91% (95% CI, 79-97%), specificity of 89% (95% CI, 81-93%), an LR+ of 8.2 and an LR- of 0.09. For endometriosis of rectovaginal septum, transvaginal ultrasonography had a sensitivity of 74% (95% CI, 64-80%), specificity of 88% (95% CI, 4-8%), an LR+ of 6.2 and an LR- of 0.3. For other locations, the sensitivity was lower (ranging from 67% to 33%) with a comparable specificity. CONCLUSIONS: This technique shows a high specificity and sensitivity in the detection of vaginal and rectovaginal endometriosis. Good specificity associated with a lower sensitivity was obtained in the diagnosis of deep endometriosis of uterosacral ligaments, rectosigmoid involvement or anterior deep endometriosis.

Bull Acad Natl Med. 2008 Jan;192(1):133-44; discussion 144-7.

[Endometriosis: a mysterious and incapacitating disorder]

[Article in French]

Belaisch J.

Maternité Pinard, Hôpital Saint-Vincent de Paul, Paris.

Endometriosis can be a highly incapacitating disorder. The only effective treatment used to be surgery (increasingly by laparoscopy), and hormone therapy was solely used as an adjuvant. Today, thanks in particular to progress in sonography and MRI, and to the growing realization of the frequent role of psychological factors, medical treatment is becoming more commonplace. Drug therapy must be envisaged in the very long term, however, because its efficacy disappears on treatment cessation.

Curr Opin Obstet Gynecol. 2008 Aug;20(4):394-9.

Deep dyspareunia: causes, treatments, and results.

Ferrero S, Ragni N, Remorgida V.

Department of Obstetrics and Gynaecology, San Martino Hospital and University of Genoa, Genova, Italy. dr@simoneferrero.com

PURPOSE OF REVIEW: We critically review the causes and treatments of deep dyspareunia. RECENT FINDINGS: Endometriosis, pelvic congestion syndrome, and interstitial cystitis have been associated with deep dyspareunia. Although medical therapies may improve deep dyspareunia in women with endometriosis, laparoscopic excision of deep endometriotic lesions has been demonstrated to improve not only deep dyspareunia but also the quality of sex life. Deep dyspareunia related to the presence of pelvic congestion syndrome should be treated by pelvic vein embolization. Intravesical therapy may be effective in treating deep dyspareunia in women with interstitial cystitis. It remains unclear whether uterine myomas and adenomyosis are causes of deep dyspareunia. SUMMARY: Treatment of deep dyspareunia should be mainly directed to causative factors; however, clinicians should keep in mind that secondary sexual dysfunction can arise from organic pelvic pathology.

Curr Opin Obstet Gynecol. 2008 Aug;20(4):325-30.

Gynaecological laparoscopy: ‘see and treat’ should be the gold standard.

Ball E, Koh C, Janik G, Davis C.

Reproductive Specialty Center and Medical College of Wisconsin, Milwaukee, Wisconsin 53211, USA. eball@mcw.edu

PURPOSE OF REVIEW: Two hundred and fifty thousand gynaecological laparoscopies are performed yearly in the UK, many of them diagnostic. Unless a patient has major endometriosis and needs advanced surgery, the Royal College of Obstetricians and Gynaecologists suggest a ‘see and treat’ policy. Thus, gynaecologists who undertake laparoscopy should be competent at performing intermediate level laparoscopic surgery, including excision of endometriosis, adhesions and benign ovarian tumours, rather than converting to laparotomy or referring patients to another unit. In order to reduce operative risk and make best use of resources, preoperative assessment should triage patients into those with unlikely pelvic pathology who do not require laparoscopy in the first instance, those with severe endometriosis, who need referral to a specialist centre and the intermediate group who is best served with a ‘see and treat’ policy. RECENT FINDINGS: Appraisal of alternatives to diagnostic laparoscopy in infertility assessment and recent reports of modified ultrasound scanning improve the predictive value and will help to avoid unnecessary laparoscopies. Preoperative predictors for severe endometriosis can determine who needs specialist referral. ‘See and treat’ laparoscopies require adequate education, and workable training methods are under investigation. SUMMARY: Negative laparoscopies should be avoided and ‘see and treat’ laparoscopy should replace diagnostic procedures. Thorough preoperative assessment helps to identify women suitable for ‘see and treat’ laparoscopy.

J Minim Invasive Gynecol. 2008 Sep-Oct;15(5):571-9. Epub 2008 Jul 26.

Early results of magnetic resonance-guided focused ultrasound surgery of adenomyosis: analysis of 20 cases.

Fukunishi H, Funaki K, Sawada K, Yamaguchi K, Maeda T, Kaji Y.

Department of Gynecology, Shinsuma General Hospital, and Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan. fukunish@iris.eonet.ne.jp

STUDY OBJECTIVE: To evaluate the thermal ablative effects of magnetic resonance-(MR) guided focused ultrasound surgery (MRgFUS) on adenomyosis and to assess improvement in clinical parameters. DESIGN: Twenty patients with adenomyosis were treated with MRgFUS. Extensive adenomyosis (6 cases) was treated with 2 applications. Uterine volume was evaluated by MR imaging before and immediately after MRgFUS. Ablation of adenomyosis and the architecture of nonperfused areas were evaluated immediately after MRgFUS. Improvement in patient symptoms was assessed through the symptom severity score questionnaire (Canadian Task Force classification II-3). SETTING: Department of gynecology at a Japanese general hospital. PATIENTS: Premenopausal women at least 18 years of age with symptomatic adenomyosis. INTERVENTIONS: Thermal ablation by MRgFUS. MEASUREMENTS AND MAIN RESULTS: We classified the nonperfused lesions on contrast-enhanced MR images immediately after MRgFUS into 3 types: lesions with round margins (type R), serrated margins (type S), and honeycomb architecture (type H). Type R was the most common (16/20 patients). Most adenomyosis lesions could be sufficiently ablated close to the serosal surface or to the endometrium by MRgFUS. The mean uterine volume 6 months after therapy was decreased by 12.7%. Symptom severity score improved significantly during 6 months of follow-up. No serious complications were observed. CONCLUSION: These early results indicate the safe and effective ablation of adenomyosis tissue by MRgFUS. The procedure also resulted in the improvement in clinical symptoms during the 6 months of follow-up.

J Endourol. 2008 Aug;22(8):1725-9.

Comparison of virtual cystoscopy and transabdominal ultrasonography with conventional cystoscopy for bladder tumor detection.

Lopes RI, Nogueira L, Albertotti CJ, Takahashi DY, Lopes RN.

Sociedade Beneficente de Senhoras Hospital Sírio Libanês, São Paulo, Brazil. robertoiglesias@terra.com.br

PURPOSE: We compare virtual cystoscopy (VC) and transabdominal ultrasonography (US) with conventional cystoscopy (CC),the gold standard, for detection of bladder tumors. PATIENTS AND METHODS: Forty-five patients suspected to have bladder neoplasms were evaluated prospectively.They underwent transabdominal US, followed by VC and CC. We compared sensitivity and specificity of US and VC and their positive and negative likelihood ratios. US and VC detection rates for tumors <or= 1 cm and tumors larger than 1 cm were compared. Histologic grade and multiplicity were correlated to detection rate. RESULTS: In the study population of 33 men and 12 women, mean age was 67.1 +/-10.9 years. Thirty-nine lesions were observed on VC and 26 lesions were observed on US of the 41 neoplasms detected at CC. Transitional bladder cancer was present in 75.6% of cases, chronic cystitis in 9.75%, endometriosis in 4.9%, and other conditions accounted for 9.75%. Thirty-one tumors were polypoid and nine were sessile; 61% were larger than 1 cm and 39% were <or=1 cm. Both US and VC 91.2% specificity, but sensitivity was better for VC (95.1%) than for US (63.4%). Multiple tumors had a better detection rate by both methods (p < 0.001). Histologic grade was positively correlated to detection rate for US (p < 0.01) but not for VC. VC was more accurate in detection of polypoid tumors compared with US (p < 0.05). CONCLUSIONS: VC showed better accuracy for detection of bladder neoplasms, especially in tumors smaller than 1 cm and for polypoid lesions.

J Am Coll Surg. 2008 Aug;207(2):205-9. Epub 2008 May 19.

Laparoscopic disk resection for bowel endometriosis using a circular stapler and a new endoscopic method to control postoperative bleeding from the stapler line.

Landi S, Pontrelli G, Surico D, Ruffo G, Benini M, Soriano D, Mereu L, Minelli L.

Department of Obstetrics and Gynecology, Ospedale Sacro Cuore, Negrar (Verona), Italy.

BACKGROUND: Complete laparoscopic excision of endometriosis offers good longterm symptomatic relief, especially for those with severe or debilitating symptoms. Intestinal endometriosis affect between 3% and 36% of women with endometriosis and 50% of women with disease severe enough that intestinal surgery, with or without intestinal segmental resection, may be required. STUDY DESIGN: Between January 2003 and September 2006, we performed 35 laparoscopic complete excisions of endometriosis with full thickness disk resections of bowel endometriosis using the CEEA stapler (US Surgical) inserted transanally. RESULTS: The endometriotic nodule of the bowel was completely removed in all patients. No major or minor surgical complications occurred during the primary surgical procedure. One patient underwent a diverting temporary ileostomy because of air loss after insufflation of the rectosigmoid colon, which was closed successfully 1 month after surgery. In three of seven cases of rectal bleeding from the stapler line, for the first time, we successfully used conservative endoscopic management. CONCLUSIONS: In properly selected patients, full thickness disk excision using a circular stapler is a feasible procedure that avoids the potential morbidities of a low anastomosis. We suggest conservative management by endoscopic hemostasis before referring patients for a new operation in cases of rectal bleeding from the anastomotic site.

Hum Reprod. 2008 Nov;23(11):2466-74. Epub 2008 Jul 24.

Intraperitoneal inflammation decreases endometriosis in a mouse model.

Nowak NM, Fischer OM, Gust TC, Fuhrmann U, Habenicht UF, Schmidt A.

GDD-TRG Women’s Healthcare, Bayer Schering Pharma AG, Berlin, Germany.

BACKGROUND: The role of the immune system in the pathogenesis of endometriosis remains elusive. It has been shown that patients have an altered peritoneal environment with increased levels of inflammatory cytokines, activated macrophages and reduced clearance of retrogradely transported endometrial fragments. However, it is not known if this unique inflammatory situation is cause or consequence of endometriosis. This study investigates the impact of a pre-existing peritoneal inflammation on endometriosis establishment in a mouse model. METHODS: Endometriosis was induced by intraperitoneal injection of enhanced green fluorescent protein (EGFP)-expressing endometrium in mice. In parallel, a peritonitis model was established via intraperitoneal injection of thioglycolate medium (TM). Finally, endometriosis was induced in the inflamed peritoneal cavity and lesion establishment as well as morphological and histological characteristics were analysed. RESULTS: Induction of endometriosis in an inflamed peritoneal cavity resulted in fewer lesions and significantly lower sum of lesion surface area per mouse in the TM-treated group. Additionally, a higher amount of non-attached debris could be detected in the peritoneal cavity of TM-treated mice. CONCLUSIONS: An intraperitoneal inflammation decreases endometriosis establishment in this mouse model. Thus, a pre-existing peritoneal inflammation might not be a factor favouring the development of endometriosis.

J Gynecol Obstet Biol Reprod (Paris). 2008 Dec;37(8):796-8. Epub 2008 Jul 23.

[Ileocecal intussusception secondary to a cecal endometriosis]

[Article in French]

Denève E, Maillet O, Blanc P, Fabre JM, Nocca D.

Service de chirurgie digestive II, hôpital Saint-Eloi, CHU de Montpellier, avenue Bertin-Sans, 34295 Montpellier, France. eric.deneve@free.fr

We report the case of a 43-year-old woman, who presented a complete and non-reductible ileo-cecal intussusception with pre-occlusion. An ileocecal resection with ileocolic anastomosis was performed. The pathologic examination confirmed the diagnosis of colic endometriosis with transmural lesions, causing the intussusception. Altough the digestive endometriosis is quite classical and well-known, particulary with vermiform appendix and rectosigmoïd involvement, ileo-cecal intussusception secondary to endometriosis is rare.

Mol Hum Reprod. 2008 Sep;14(9):531-8. Epub 2008 Jul 23.

Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis.

Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW.

Molecular Epidemiology, Queensland Institute of Medical Research, Brisbane, Queensland 4029, Australia. zhen.zhao@qimr.edu.au

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein suspected to be involved in the pathogenesis of endometriosis by establishing a new blood supply to the human exfoliated endometrium. Several transcription factor-binding sites are found in the VEGF 5′-untranslated region and variation within the region increases the transcriptional activity. Six previous studies which tested between one and three single nucleotide polymorphisms (SNPs) in samples comprising 105-215 cases and 100-219 controls have produced conflicting evidence for association between the SNPs in the VEGF region and endometriosis. To further investigate the reported association between VEGF variants and endometriosis, we tested the four VEGF polymorphisms (-2578 A/C, rs699947; -460 T/C, rs833061; +405 G/C, rs2010963 and +936 C/T, rs3025039) in a large Australian sample of 958 familial endometriosis cases and 959 controls. We also conducted a literature-based review of all relevant association studies of these VEGF SNPs in endometriosis and performed a meta-analysis. There was no evidence for association between endometriosis and the VEGF polymorphisms genotyped in our study. Combined association results from a meta-analysis did not provide any evidence for either genotypic or allelic association with endometriosis. Our detailed review and meta-analysis of the VEGF polymorphisms suggests that genotyping assay problems may underlie the previously reported associations between VEGF variants and endometriosis.

Br J Hosp Med (Lond). 2008 Jun;69(6):314-5.

Do we know what causes endometriosis?

Wagstaff D, Becker CM.

 

Ethn Dis. 2008 Spring;18(2 Suppl 2):S2-20-4.

Visceral sensory neurons that innervate both uterus and colon express nociceptive TRPv1 and P2X3 receptors in rats.

Chaban VV.

Department of Biomedical Sciences, Charles R. Drew University of Medicine and Science, 1731 E 120th St, Los Angeles, CA 90095, USA. victorchaban@cdrewu.edu

In women, clinical studies suggest that functional pain syndromes such as irritable bowel syndrome, interstitial cystitis, and fibromyalgia, are co-morbid with endometriosis, chronic pelvic pain, and others diseases. One of the possible explanations for this phenomenon is visceral cross-sensitization in which increased nociceptive input from inflamed reproductive system organs sensitize neurons that receive convergent input from an unaffected visceral organ to the same dorsal root ganglion (DRG). The purpose of this study was to determine whether primary sensory neurons that innervate both visceral organs–the uterus and the colon–express nociceptive ATP-sensitive purinergic (P2X3) and capsaicin-sensitive vanilloid (TRPV1) receptors. To test this hypothesis, cell bodies of colonic and uterine DRG were retrogradely labeled with fluorescent tracer dyes micro-injected into the colon/rectum and uterus of rats. Ganglia were harvested, cryo-protected, and cut in 20-microm slices for fluorescent microscopy to identify positively stained cells. Up to 5% neurons were colon-specific or uterus-specific, and 10%-15% of labeled DRG neurons innervate both viscera in the lumbosacral neurons (L1-S3 levels). We found that viscerally labeled DRGs express nociceptive P2X3 and TRPV1 receptors. Our results suggest a novel form of visceral sensory integration in the DRG that may underlie co-morbidity of many functional pain syndromes.

Gynecol Obstet Invest. 2008;66(4):241-7. Epub 2008 Jul 22.

Decidualization of ovarian endometriosis during pregnancy mimicking malignancy: report of three cases with a literature review.

Machida S, Matsubara S, Ohwada M, Ogoyama M, Kuwata T, Watanabe T, Izumi A, Suzuki M.

Department of Obstetrics and Gynecology, Jichi Medical University, Tochigi, Japan.

BACKGROUND: Intracystic papillary excrescence is a characteristic morphological feature of ovarian malignancy. A few recent reports have demonstrated that ovarian endometriotic cysts, undergoing decidualization during pregnancy, occasionally show excrescence, necessitating surgery during pregnancy; however, this phenomenon is not well recognized among clinicians. CASES: Three pregnant women with decidualized ovarian endometriosis showed excrescence. Both ultrasound and magnetic resonance imaging (MRI) preoperatively suggested the presence of underlying ovarian endometriotic cysts in 2 women, but not in the other. Intracystic papillary excrescence prompted us to perform laparotomy at 14, 14, and 19 weeks of pregnancy, respectively, with 1 woman aborting in the 21st week, and with 2 delivering healthy term infants. Histological examination confirmed the diagnosis of decidualized ovarian endometriotic cysts in all 3 patients. CONCLUSIONS: We provide the first report of pregnant women in whom excrescence occurred from ovarian endometriotic cysts without preoperative evidence. Decidualized ovarian endometriosis, even without preoperative morphological features of endometriosis, should be added to the differential diagnosis of ovarian malignancy during pregnancy. (c) 2008 S. Karger AG, Basel.

Gynecol Obstet Invest. 2008;66(3):209-13. Epub 2008 Jul 22.

Co-occurrence of atypical endometriosis, subserous uterine leiomyomata, sactosalpinx, serous cystadenoma and bilateral hemorrhagic corpora lutea in a perimenopausal adipose patient taking tamoxifen (20 mg/day) for invasive lobular breast cancer.

Ebert AD, Rosenow G, David M, Mechsner S, Magalov IS, Papadopoulos T.

Department of Gynecology and Obstetrics, Endometriosis Center Level III, Campus Humboldt, Vivantes-Network for Health, Berlin, Germany. andreas.ebert@vivantes.de

BACKGROUND: For women taking tamoxifen, recent data strongly support the estrogen agonist role of tamoxifen as a causal factor for the increased risk of endometriosis, but also of leiomyomata, endometrial polyps, and endometrial hyperplasia. CASE REPORT: A 54-year-old perimenopausal woman on tamoxifen (20 mg/day), gravida 0, with surgically treated invasive lobular breast cancer and extensive lobular carcinoma in situ (pT2 (m) pN0 (snl) pL0 G2 pTis (LCLIS) R0 M0 Ki-67 1%, ER+, PR+, Her-2-neu-negative) was referred for evaluation of a pelvic mass. The ultrasonographic examination showed a regular endometrium of less than 6 mm thickness, a uterine myoma (approximately 3 cm in diameter), a right-sided sactosalpinx (7.7 x 3.6 x 5.7 cm), an ovarian cyst on the right side (approximately 4 cm), and a left-sided ovarian cyst (approximately 3 cm in diameter) without any malignancy criteria. The CA-125 level was normal (9.4 U/ml). With the exception of a decreased serum progesterone level; the endocrine status showed no sign of ovarian insufficiency (LH 5.6 mIU/ml, FSH 9.0 mIU/ml, estradiol 103.7 pg/ml, progesterone 1.51 ng/ml, testosterone 0.11 ng/ml, DHEA-S 62.3 microg/dl, SHBG 64.39 nmol/l, free androgen index 0.6). During laparoscopy 2 uterine subserous leiomyomata, a right-sighted sactosalpinx, bilateral ovarian cysts, and an extended polypoid, vascularized endometriosis of the bladder peritoneum, the pelvic wall and Douglas pouch were found. Complete pelvic deperitonealization, bilateral adnexectomy, and also enucleation of the 2 leiomyomata were performed. RESULTS: Pathological examination confirmed the sactosalpinx. In the cystic ovary (right side), a serous cystadenoma close to a hemorrhagic corpus luteum (HCL) was diagnosed. The left ovary showed another HCL. The removed leiomyomata did not show atypia or significant mitotic activity. The endometriotic lesions presented strong expression of the estrogen receptor, the progesterone receptor, and the proliferation marker MIB-1. In addition, there was no HER-2-neu expression. A switch to the aromatase inhibitor letrozol was recommended. CONCLUSION: The possibility of tamoxifen-induced or tamoxifen-driven endometriosis in peri- or postmenopausal patients with breast cancer should be considered. Copyright 2008 S. Karger AG, Basel.

J Obstet Gynaecol Can. 2008 Jul;30(7):555, 556.

Catamenial sciatica.

[Article in English, French]

Nevin Lam AC, Singh SS, Leyland NA.

Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada.

Akush Ginekol (Sofiia). 2008;47(2):30-8.

[Frequency of gynecological morbidity and chronic pelvic pain in the Gynecological Clinic, UMPHAT “Dr. G. Stransky” – Pleven]

[Article in Bulgarian]

Lukanova M, Miteva I, Gorgioski S, Popov I, Tsafarov M.

OBJECTIVE: By setting the structure of gynaecological morbidity to determine the frequency of chronic pelvic pain /CPP/ and the most common diseases, presented with CPP. MATERIALS AND METHODS: A prospective study was conducted in the Gynaecological Clinic at the Department of Obstetrics and Gynaecology, Medical University-Pleven in the period 01.03.2004-01.07.2007. During that period, 4168 women were consecutively admitted in the Clinic. The object of the study were patients with leiomyomatosis /L/, endometriosis /E/, adenomyosis /A/, pelvic congestion syndrome/PCS/, Allen-Masters syndrome/AMS/, pelvic inflammatory disease /PID/ and adhesion syndrome /AS/. They were divided in groups according to age, type of disease and presence of CPP. The following methods were used for the purpose of the study: documentary method, R-AFS classification of E, inquiry method-by a questionnaire/form/, based on instruments for pain assessment, which are accepted worldwide /visual analogue scale, etc. RESULTS AND DISCUSSION: Among all 1357 women included in the study, the most common diseases were L, followed by E and A, and AS. Comparatively lower frequency was determined for PCS and AMS. In almost one-third of the women in the study were admitted in the Clinic for diagnostic specification or operative treatment because of CPP. The most frequently defined reason for it were E, L and AS, and in a smaller part of patients-PCS and AMS. CONCLUSION: From the analysis we made, we concluded that CPP was very often polyetiologically determined, which was assessed by some invasive methods.

Gynecol Oncol. 2008 Sep;110(3):336-44. Epub 2008 Jul 18.

Prognostic implication of endometriosis in clear cell carcinoma of the ovary.

Orezzoli JP, Russell AH, Oliva E, Del Carmen MG, Eichhorn J, Fuller AF.

Gillette Center for Gynecologic Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. jporezzoli@inbox.com

OBJECTIVE: The aim of this study is to investigate whether the presence of endometriosis is a prognostic factor in patients diagnosed with clear cell carcinoma (CCC) of the ovary. METHODS: Retrospective chart review was performed to all patients diagnosed with CCC and endometriosis between 1975 and 2002. All pathology reports were reviewed and slides were reviewed when available. Cox regression analysis and Kaplan-Meier test were used to calculate survival prognostic factors. The level of significance was set at 0.05. RESULTS: Eighty-four patients with CCC were identified with a 49% rate of coexisting endometriosis. Patients with tumors arising in endometriosis (n=15), with endometriosis found elsewhere in the specimen (n=26), and those without endometriosis (n=43) were analyzed comparatively. Patients with CCCs arising in endometriosis were 10 years younger (95% C.I. 0.6-18 years) than those with CCC not arising in endometriosis (P<0.05). Patients with endometriosis anywhere in the surgical specimen presented at early stage 66% of the times versus 42% for patients without endometriosis (P<0.05). Median overall survival (OS) for patients with endometriosis was 196 months (95% C.I. 28-363) versus 34 months (95% C.I. 13-55) for patients without endometriosis (P=0.01). Advanced tumor stage at diagnosis (HR 13, 95% C.I. 5-29, P=0.001) and absence of endometriosis (HR 2, 95% C.I. 1-3.9, P=0.03) were the only significant prognostic factors associated with poor survival. Disease recurrence or death among optimally and completely cytoreduced patients was 31% and 59% for those with and without endometriosis respectively (P>0.05). CONCLUSIONS: Our study suggests that the presence of endometriosis in patients with CCC of the ovary is associated with progression free and OS advantages with no difference in initial resectability.

Am J Obstet Gynecol. 2008 Nov;199(5):e16-7; author reply e17-8. Epub 2008 Jul 17.

Comment on:

Am J Obstet Gynecol. 2008 May;198(5):504.e1-5.

Oversight or Trompe l’oeil?

Sun Q.

 

Adv Exp Med Biol. 2008;630:112-32.

Aromatase expression in women’s cancers.

Bulun SE, Simpson ER.

Department of Obstetric and Gynecology, Northwestern University, Chicago, IL 60611, USA. sbulun@northwestern.edu

Estrogen has been positively linked to the pathogenesis and growth of three common women’s cancers (breast, endometrium and ovary). A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less dear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue specific promoters distributed over a 93 kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. In cancers ofbreast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter 1.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE2 via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE2 secreted by malignant epithelial cells, activation of PKC potentiates cAMP-PKA-dependent induction ofaromatase. Thus, inflammatory substances such as PGE2 may play important roles in inducing local production of estrogen that promotes tumor growth.

Hum Reprod. 2008 Oct;23(10):2202-9. Epub 2008 Jul 16.

Estrogen and progestogen receptor positive endometriotic lesions and disseminated cells in pelvic sentinel lymph nodes of patients with deep infiltrating rectovaginal endometriosis: a pilot study.

Mechsner S, Weichbrodt M, Riedlinger WF, Bartley J, Kaufmann AM, Schneider A, Köhler C.

Department of Gynecology, Endometriosis Research Center Charité, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. sylvia.mechsner@charite.de

BACKGROUND: Deep infiltrating endometriosis (DIE) shows similarities to malignant diseases. A recent study involving DIE patients found endometriosis in mesorectal lymph nodes (LNs) after segmental bowel resection. However, it is unclear whether this observation is a local phenomenon or a sign of systemic disease. Therefore, we conducted a prospective study to investigate the occurrence of endometriosis in pelvic sentinel lymph nodes (SLNs) in patients with DIE. METHODS: Fourteen patients underwent primary surgery for symptomatic DIE. Combined vaginal laparoscopic-assisted resection of the rectovaginal septum was performed. Dye was injected into the visible/palpable nodule. SLNs were removed from the iliac region. In order to identify endometriotic cells, immunohistochemical analysis of estrogen and progestogen receptors, CD10 and cytokeratin was performed. RESULTS: In 12 out of 14 patients with DIE, SLNs were detected. The localization of the SLN followed the typical LN spread of the upper vagina. In three patients, we could detect typical endometriotic lesions in the LNs. Ten out of 12 (83.3%) SLNs showed disseminated estrogen and/or progestogen positive cells. CONCLUSIONS: By using immunohistochemistry, we could demonstrate endometriotic lesions and endometriotic-like cells in pelvic SLNs of patients with DIE suggesting the potential for lymphatic spread of the disease.

Fertil Steril. 2008 Oct;90(4):994-9. Epub 2008 Jul 16.

Serum interleukin-8 levels are elevated in patients with ovarian endometrioma.

Ohata Y, Harada T, Miyakoda H, Taniguchi F, Iwabe T, Terakawa N.

Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan.

OBJECTIVE: To determine whether serum interleukin (IL)-8 concentration can be measured in patients with ovarian endometrioma and whether this measurement is a useful tool in diagnosing this disease. DESIGN: A controlled clinical study and an in vitro study. SETTING: Department of Obstetrics and Gynecology, Tottori University, Japan. PATIENT(S): Seventy patients with ovarian endometrioma and 21 patients with benign ovarian cyst. INTERVENTION(S): Laparoscopic surgery or laparotomy for ovarian endometriomas or benign ovarian cyst was performed. Preoperative blood samples were obtained. Endometriotic stromal cells obtained from nine patients with endometrioma were cultured. MAIN OUTCOME MEASURE(S): Interleukin-8 concentration in the serum or supernatant of the cell culture was measured with use of ELISA. RESULT(S): The serum concentration of IL-8 in patients with endometrioma was significantly higher than in patients with benign ovarian cyst. The serum IL-8 threshold (25 pg/mL) had a higher sensitivity (71.4%) for diagnosing ovarian endometrioma than did serum CA-125 level. The increased rates of IL-8 concentration in the culture supernatants after adding tumor necrosis factor alpha were significantly higher in patients whose serum IL-8 levels were >or=25 pg/mL than in those with levels <25 pg/mL. CONCLUSION(S): Measuring of serum IL-8 concentration may be a valuable tool in diagnosing endometriosis.

Saudi Med J. 2008 Jul;29(7):1044-7.

Endometrioid adenocarcinoma 13 years after total abdominal hysterectomy and bilateral salpingo-oophorectomy.

Al-Talib A, Gilbert L, Arseneau J.

Division of Gynecologic Oncology, Royal Victoria Hospital, McGill University, Montreal, Canada. abuamer_t@yahoo.com

Malignant transformation is an infrequent complication of endometriosis. As endometriosis is an ectopic endometrium, hyperestrogenism may cause hyperplasia or transformation into cancer. We describe a case of a 68-year-old woman who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for endometriosis. She was subsequently placed on estrogen-only replacement therapy. She presented with left-sided pelvic mass and shortness of breath. Computed tomography of chest, pelvis, and abdomen, demonstrated right-sided pleural effusion and soft tissue mass in the pelvis. Pleural effusion was tapped and biopsy from the peritoneal mass showed metastatic adenocarcinoma; immunohistochemistry findings favored endometrioid adenocarcinoma. She was treated by 6 cycles of Carboplatin/Paclitaxel and responded well. Unopposed estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestins to estrogen replacement therapy should be considered in women who have undergone hysterectomy with oophorectomy due to endometriosis.

J Minim Invasive Gynecol. 2008 Sep-Oct;15(5):538-40. Epub 2008 Jul 10.

Endometriomas as a marker of disease severity.

Banerjee SK, Ballard KD, Wright JT.

Centre for Endometriosis and Pelvic Pain, St. Peter’s Hospital, Women’s Health Research Unit, Postgraduate Medical School, University of Surrey, Surrey, United Kingdom.

STUDY OBJECTIVE: Although superficial endometriosis can be treated effectively and safely by most gynecologic surgeons, deep infiltrating disease (DIE) needs to be treated in specialist endometriosis centers. For women to be treated in the most appropriate setting, it is necessary to identify if they have DIE. DESIGN: Prospective observational study (Canadian Task Force classification II-2). SETTING: Dedicated pelvic pain clinic attracting both secondary and tertiary referrals. PATIENTS: A total of 295 women with histologically confirmed endometriosis. INTERVENTIONS: Prospective intraoperative data were collected to investigate the role of endometriomas as a marker for DIE, and in particular, rectosigmoid disease. MEASUREMENTS AND MAIN RESULTS: In all, 61 (21%) women had an endometrioma. A significantly greater proportion of women with an endometrioma had accompanying endometriotic disease affecting the bowel compared with women without an endometrioma (77% vs 21%; p<.001). A strong relationship existed between presence of endometrioma and posterior cul-de-sac obliteration, rectosigmoid disease, and involvement of the seromuscular layer of the bowel. The presence of an endometrioma significantly increased the probability of having rectosigmoid disease, with a positive likelihood ratio of 6.96 (95% CI; 4.04-12.00). However, the absence of an endometrioma did not preclude having rectosigmoid disease, with a negative likelihood ratio of 0.55 (95% CI; 0.45-0.67). CONCLUSION: Although endometriomas provide a useful marker for DIE, the absence of an endometrioma does not preclude the presence of DIE, although a significantly lower proportion of women without an endometrioma will have DIE when compared with women with an endometrioma.

J Clin Endocrinol Metab. 2008 Jul;93(7):2439-46.

Update in female reproduction: a life-cycle approach.

Barbieri RL.

Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. rbarbieri@partners.org

CONTEXT: Female reproduction spans a developmental life arc from fetal life and childhood, through puberty to the reproductive years, and, finally, ovarian follicle depletion and the onset of menopause. OBJECTIVE: This invited review highlights a selection of reports from leading journals over the past 2 yr that have significantly advanced our understanding of female reproduction from conception to menopause. SYNTHESIS: During fetal life, in utero exposures may be important determinants of later pubertal and adult endocrine physiology. Epigenetic mechanisms are likely involved in the fetal programming of adult endocrine function. With regards to the polycystic ovary syndrome, recent clinical trials have confirmed the central role of clomiphene for ovulation induction in women with this disease. In addition, an expert panel has recommended that all women with polycystic ovary syndrome have a glucose tolerance test because of the high prevalence of impaired glucose tolerance in this population. In menopausal women the precise impact of estrogen therapy on cardiovascular biology remains to be delineated fully. Evolving data indicate that when initiated near the onset of menopause, estrogen therapy has fewer cardiovascular risks than when it is administered decades after the menopause. CONCLUSIONS: The essence of reproduction is the successful transmission of germ-line DNA to a succeeding generation. Advances in genetics and endocrinology are converging to advance significantly our understanding of the biology of reproduction and our ability to influence reproductive processes. These advances will translate into new treatments for the prevalent medical problems of reproduction.

Expert Opin Investig Drugs. 2008 Aug;17(8):1187-202.

New drugs in development for the treatment of endometriosis.

Fedele L, Somigliana E, Frontino G, Benaglia L, Vigano P.

Fondazione IRCCS Ospedale Maggiore Policlinico, Obstetrics and Gynecology, Mangiagalli e Regina Elena, Via Commenda 12, 20122 Milano, Italy. luigi.fedele@unimi.it

Endometriosis is a common and enigmatic disease causing pelvic pain and infertility. Current treatment is mainly based on the use of surgery and ovarian suppressive agents. There is in particular the need for new therapeutic options able to allow a normal menstrual cycle to occur and also consent pregnancy. In the present review, we aimed to give a concise and practical overview in order to allow the clinician to clearly understand the level of development of these drugs. We have presented only treatments supported by in vivo researches with a special attention to studies in humans. Results show appealing new possibilities are emerging from agents counteracting the endometriosis-associated inflammation. Recent data also suggests that there is still the opportunity to refine the use of already available agents.

Endoscopy. 2008 Jul;40(7):576-80.

How do gynecologists feel about transvaginal NOTES surgery?

Thele F, Zygmunt M, Glitsch A, Heidecke CD, Schreiber A.

Department of Gynecology and Obstetrics, Greifswald University Hospital, Ernst-Moritz-Arndt University of Greifswald, Germany.

BACKGROUND: Natural-orifice transluminal endoscopic surgery (NOTES) is regarded as safer and less invasive than laparoscopic surgery. However, there has been no documentation of the opinions of surgically active, experienced gynecologists about the indications, contraindications, risks, and complications of transvaginal access. METHODS: A two-page questionnaire was distributed to the heads of the gynecological departments at 181 university and major teaching hospitals across Germany, Austria, and Switzerland. Fifty-two questionnaires (28.7 %) were returned and evaluated. The questionnaire contained ten questions, four of which were yes/no questions and another five of which allowed between four and seven answers. The questionnaire contained one additional open question. RESULTS: Of the respondents, 69.2 % classified transvaginal access for extrapelvic abdominal surgery as ethical; the remaining 30.8 % described it as experimental. Only 28.8 % would recommend NOTES to their patients if NOTES presented the same surgical risks as the laparoscopic approach. When asked about NOTES-associated complications, 73.1 % mentioned the risk of infection, 61.5 % visceral lesions, 44.2 % infertility, and 34.6 % adhesions. In terms of long-term problems, gynecologists are concerned about dyspareunia and infertility. Adopting their patients’ point of view, 17.3 % voted the lack of scarring compared to laparoscopy as important and 57.6 % as unimportant. CONCLUSIONS: While transvaginal NOTES is argued to be a promising access for scarless surgery, gynecologists mention postoperative infection, visceral lesions, infertility, and adhesions as conceivable complications. Since long-term experience has not yet been achieved, potential problems such as dyspareunia, infertility, and the spread of pre-existing endometriosis remain definitely conceivable complications.

Tidsskr Nor Laegeforen. 2008 Jun 26;128(13):1558.

Comment on:

Tidsskr Nor Laegeforen. 2008 Jun 26;128(13):1557.

[A shorter way to the diagnosis of endometriosis]

[Article in Norwegian]

Moen MH.

Institutt for laboratoriemedisin, barneog, kvinnesykdommer, Norges teknisk-naturvitenskapelige universitet og Kvinneklinikken, St. Olavs Hospital, 7006 Trondheim. mette.moen@ntnu.no

Tidsskr Nor Laegeforen. 2008 Jun 26;128(13):1557.

Comment in:

Tidsskr Nor Laegeforen. 2008 Jun 26;128(13):1558.

[A relative’s dream]

[Article in Norwegian]

Brekke TK.

tonekindbrekke@hotmail.com

Hum Reprod. 2008 Oct;23(10):2308-18. Epub 2008 Jul 4.

Epigallocatechin-3-gallate inhibits estrogen-induced activation of endometrial cells in vitro and causes regression of endometriotic lesions in vivo.

Laschke MW, Schwender C, Scheuer C, Vollmar B, Menger MD.

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

BACKGROUND: Epigallocatechin-3-gallate (EGCG), the major component of green tea, is a pleiotropic substance, which may inhibit tumor growth via multiple intracellular signaling pathways. Herein, we studied whether EGCG may also be effective in the treatment of endometriosis. METHODS: We investigated the effect of EGCG on activation by estradiol (E(2)), proliferation and vascular endothelial growth factor (VEGF) expression of isolated hamster endometrial stromal cells and glandular cells in vitro using the water-soluble tetrazolium (WST)-1 colorimetric assay and western blot analysis. In the dorsal skinfold chamber model of Syrian golden hamsters, which were treated for 14 days with EGCG or vehicle, we further analyzed angiogenesis, blood perfusion and tissue integrity of both endometriotic lesions and ovarian follicles by intravital fluorescence microscopy and histology. RESULTS: We found that EGCG suppresses E(2)-stimulated activation, proliferation and VEGF expression of endometrial cells in vitro (all P < 0.05). Furthermore, EGCG selectively inhibited angiogenesis and blood perfusion (P < 0.05) of endometriotic lesions in vivo without affecting blood vessel development in ovarian follicles. Histology confirmed that EGCG-treatment induces regression of the endometriotic lesions. CONCLUSIONS: Our data indicate that EGCG might be a promising therapeutic agent in the treatment of endometriosis, preventing the establishment of new endometriotic lesions.

J Minim Invasive Gynecol. 2008 Jul-Aug;15(4):505-7.

Ovarian remnant syndrome at the port site.

Chao HA.

Branch of Obstetrics and Gynecology, Dou-Liou Branch of National Cheng Kung University Hospital, Yunlin, Taiwan. chao531018@hotmail.com

Ovarian remnant syndrome is a rare gynecologic complication, mostly induced by difficult salpingo-oophorectomy with the residual ovarian tissue on the pelvic side wall. This is a report of a rare case of ovarian remnant syndrome at a port site after laparoscopic oophorectomy and a review of the related literature. A 22-year-old virgin had a laparoscopic oophorectomy for an endometrioma 5 years earlier. Postoperatively, she visited gynecologic clinics for a frequent painful sensation at the left port site. After sonographic examination and under the impression of a recurrent endometrioma, laparotomy and cyst excision were performed. Surprisingly, ectopic ovary was diagnosed by the pathologist. Review of the literature revealed ovarian remnant implantation at a port site as a very rare type of ovarian remnant syndrome. During laparoscopic oophorectomy in a woman without sexual exposure who is not a good candidate for culdotomy, the removal of the excised ovary through the port site is sometimes difficult and residual ovarian tissue implantation may occur. There are many methods to reduce the risk of port-site seeding, which we must keep in mind and execute to prevent such a complication.

J Minim Invasive Gynecol. 2008 Jul-Aug;15(4):494-7.

The pelvic uterus-like mass–a primary or secondary Müllerian system anomaly?

Kaufman Y, Lam A.

Centre for Advanced Reproductive Endosurgery, Sydney, Australia.

The pelvic uterus-like mass is a rare phenomenon in which an extrauterine mass, comprised of smooth muscle and a central cavity lined by endometrium, is found within the pelvis. The mass is associated with endometriosis and in some of the cases with congenital Müllerian malformations. There is an ongoing debate whether the finding is a result of smooth muscle metaplasia or a remnant of a Müllerian system defect. We present 2 distinct cases of a uterus-like mass.

J Pathol. 2008 Sep;216(1):103-10.

Clear-cell adenofibroma can be a clonal precursor for clear-cell adenocarcinoma of the ovary: a possible alternative ovarian clear-cell carcinogenic pathway.

Yamamoto S, Tsuda H, Takano M, Hase K, Tamai S, Matsubara O.

Department of Basic Pathology, National Defence Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.

Several studies have reported that ovarian clear-cell adenocarcinoma can be derived from endometriosis. Although the clear-cell adenofibroma (CCAF), a major form of benign and borderline ovarian clear-cell tumour, has been suggested as another precursor for clear-cell adenocarcinoma (CCA), there is no supportive genetic evidence for this presumption. To examine the genetic linkage between CCAF and CCA of the ovary, we conducted allelotype analysis for both CCAF and adjacent CCA components in 14 cases of CCA associated with benign CCAF and/or borderline CCAF. DNA isolated from laser-microdissected tissue was subjected to polymerase chain reaction and analysis for loss of heterozygosity (LOH), using 17 polymorphic markers located on 11 chromosomal arms: 1p, 5q, 8p, 9p, 9q, 10q, 11q, 13q, 18q, 19p and 22q. For all informative loci, the frequency of LOH in adenocarcinoma was 49% (54/110 loci), and was significantly higher than those in the components of benign CCAF (22%, 20/92 loci) and borderline CCAF (30%, 25/83 loci) (chi(2) test; p<0.05, respectively). The concordance rate in allelic patterns at all informative loci was 74% between benign CCAF and adenocarcinoma components, 81% between borderline CCAF and adenocarcinoma components, and 95% between benign CCAF and borderline CCAF components. Furthermore, between CCAF and adenocarcinoma components, an identical LOH pattern, involving the same alleles, was found in 13 (93%) of 14 cases at one or more chromosomal loci, and estimation of probability indicated that these events were very unlikely to have occurred by chance. Among the markers examined, LOHs on 5q, 10q and 22q were frequent in both CCAF and adenocarcinoma components, whereas LOHs on 1p and 13q were rare in CCAF components but frequent in adenocarcinoma components. These findings suggest that CCAF can be a clonal precursor for ovarian clear-cell adenocarcinoma.

Am J Pathol. 2008 Aug;173(2):463-9. Epub 2008 Jul 3.

Interleukin-4 stimulates proliferation of endometriotic stromal cells.

OuYang Z, Hirota Y, Osuga Y, Hamasaki K, Hasegawa A, Tajima T, Hirata T, Koga K, Yoshino O, Harada M, Takemura Y, Nose E, Yano T, Taketani Y.

Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Several lines of evidence indicate that the Th2 immune response is associated with endometriosis. Although an increased concentration of interleukin (IL)-4, a typical Th2 cytokine, has been reported in endometriotic tissues, the implication of this for endometriosis has not been determined. To investigate a possible role of IL-4 in the development of endometriosis, we examined the presence of IL-4-producing cells in endometriotic tissues and the effect of IL-4 on proliferation of endometriotic stromal cells. Endometriotic stromal cells were isolated from endometriotic tissues obtained from women undergoing surgery for endometrioma. Immunohistochemistry of endometriotic tissues revealed that IL-4-positive cells were abundant in the stroma. The effect of IL-4 on proliferation of endometriotic stromal cells was studied using cell counting and BrdU incorporation assays. IL-4 (0.1 to 10 ng/ml) significantly increased cell number and BrdU incorporation in a dose-dependent manner, and the proliferative effect of IL-4 was inhibited by anti-IL-4 receptor antibody. IL-4-induced activation of mitogen-activated protein kinases in endometriotic stromal cells was examined by Western blotting. IL-4 induced phosphorylation of p38 mitogen-activated protein kinase, stress-activated protein kinase/c-Jun kinase, and p42/44 mitogen-activated protein kinase and inhibitors of these kinases suppressed IL-4-induced proliferation of endometriotic stromal cells. These findings suggest that proliferation of endometriotic stromal cells induced by locally produced IL-4 is involved in the development of endometriosis.

Ultrasound Med Biol. 2008 Dec;34(12):1914-8. Epub 2008 Jul 2.

Uterine ultrasonographic changes during endometriosis treatment: a comparison between levonorgestrel-releasing intrauterine devices and a gonadotropin-releasing hormone agonist.

Manetta LA, de Paula Martins W, Rosa e Silva JC, de Sá Rosa e Silva AC, Nogueira AA, Ferriani RA.

Department of Gynecology and Obstetrics, Faculty of Medicine-Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.

We compared the effects of levonorgestrel-releasing intrauterine devices (LNG-IUD) and a gonadotropin-releasing hormone agonist (GnRHa) on uterine volume, uterine arteries pulsatility index (PI) and endometrial thickness before and after six months of endometriosis treatment. Sixty women aged 18-40 y were allocated randomly to one of two groups: LNG-IUDs were inserted in 30 women, and GnRHa monthly injections were performed on the other 30. All 60 women were submitted to transvaginal 2-D ultrasound scans on the day that the treatment started and then six months later. Measurements of uterine arteries PI, uterine volume and endometrial thickness were performed at both evaluations. The use of LNG-IUDs significantly decreased endometrial thickness (pre = 6.08 +/- 3.00 mm, post = 2.7 +/- 0.98 mm; mean +/- SD), as did the use of GnRHa (pre = 6.96 +/- 3.82 mm, post = 3.23 +/- 2.32 mm). The uterine volume decreased in the GnRHa group (pre = 86.67 +/- 28.38 cm(3), post = 55.27 +/- 25.52 cm(3)), but not in the LNG-IUD group (pre = 75.77 +/- 20.88 cm(3), post = 75.97 +/- 26.62 cm(3)). Uterine arteries PI increased for both groups; however, the increase was higher in the GnRHa group (0.99 +/- 0.84 vs. 0.38 +/- 0.84, p = 0.007; PI increase in GnRHa and in LNG-IUD groups, respectively). In conclusion, levonorgestrel released directly onto the endometrium by the LNG-IUD induced smaller uterine changes than did the hypoestrogenism induced by GnRHa. Nevertheless, both promoted similar effects on endometrial thickness.

Hum Reprod. 2008 Oct;23(10):2210-9. Epub 2008 Jul 1.

Toll-like receptor 4-mediated growth of endometriosis by human heat-shock protein 70.

Khan KN, Kitajima M, Imamura T, Hiraki K, Fujishita A, Sekine I, Ishimaru T, Masuzaki H.

Department of Obstetrics and Gynecology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. nemokhan@nagasaki-u.ac.jp

BACKGROUND: We investigated the role of human heat-shock protein 70 (Hsp70) in Toll-like receptor 4 (TLR4)-mediated growth of endometriosis. METHODS: TLR4 expression was examined in macrophages (M) isolated in primary culture from the peritoneal fluid of women with and without endometriosis. The production of a number of macromolecules by non-treated M, Hsp70-treated M and after treatment with anti-TLR4 antibody was examined by enzyme linked immunosorbent assay (ELISA). The single and combined effects of Hsp70 and lipopolysaccharide (LPS) on the growth of endometrial stromal cells were analyzed by 5-bromo-2-deoxyuridine (BrdU) incorporation study. Hsp70 levels in eutopic and ectopic endometria were measured by ELISA. RESULTS: TLR4 was detected in isolated M at protein and gene level. Hsp70 (10 microg/ml) significantly stimulated the production of hepatocyte growth factor, vascular endothelial cell growth factor, interleukin-6 and tumor necrosis factor alpha by M derived from women with endometriosis compared with M derived from women with no endometriosis (P < 0.05 for each). This effect of Hsp70 was abrogated after pretreatment of M with anti-TLR4 antibody. BrdU incorporation indicated that Hsp70 significantly enhanced the growth of endometrial stromal cells ( approximately 50% increase) from women with endometriosis compared to non-treated cells. A synergistic effect on cell proliferation was observed between exogenous Hsp70 and LPS and this was significantly suppressed by pretreatment of cells with anti-TLR4 antibody (P < 0.05). Tissue levels of Hsp70 were significantly higher in the eutopic endometria (P < 0.05) and opaque red lesions (P < 0.01) derived from women with endometriosis than from other peritoneal lesions or from women with no endometriosis. CONCLUSIONS: A prominent stress reaction was observed in blood-filled opaque red peritoneal lesions. Human Hsp70 induces pelvic inflammation and may be involved in TLR4-mediated growth of endometrial cells derived from women with endometriosis.

Cytokine. 2008 Aug;43(2):105-9. Epub 2008 Jul 1.

Cytokine and chemokine expression in a rat endometriosis is similar to that in human endometriosis.

Umezawa M, Sakata C, Tanaka N, Kudo S, Tabata M, Takeda K, Ihara T, Sugamata M.

Department of Pathology, Tochigi Institute of Clinical Pathology, Tochigi 329-0112, Japan. j3108703@ed.noda.tus.ac.jp

The pathogenesis of endometriosis, a gynecologic disorder associated with infertility, appears to involve immune responses. However, the details involved have not been clarified. In this study, we analyzed expression levels of interleukin (IL)-6, IL-10, monocyte chemoattractant protein-1, eosinophil chemotactic protein, macrophage inflammatory protein-1alpha, and regulated on activation normal T cell expressed and secreted (RANTES) and CC chemokine receptor 1 in endometriotic lesions in a rat model in which endometrium is autotransplanted onto peritoneal tissue and found that they were remarkably increased, while those of IL-2, IL-4, and interferon-gamma were not. These results were obtained in a rat model induced by autologous, not allogeneic, transplantation of endometrial epithelium to the peritoneum. Expression of these factors is consistent with that of endometriosis in humans. Therefore, this model may be useful in the investigation of the pathogenesis and treatment of endometriosis.

J Pharmacol Exp Ther. 2008 Oct;327(1):78-87. Epub 2008 Jul 1.

The translational pharmacology of a novel, potent, and selective nonsteroidal progesterone receptor antagonist, 2-[4-(4-cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982).

de Giorgio-Miller A, Bungay P, Tutt M, Owen J, Goodwin D, Pullen N.

Pfizer PGRD, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.

The progesterone receptor (PR) is an important regulator of endometrial function. Blockade of PR function has been recognized as the potential basis for preventing gynecological conditions such as endometriosis and uterine fibroids. In this study, we examine the in vitro and in vivo properties of a nonsteroidal PR antagonist, 2-[4-(4-cyano-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide (PF-02367982) in comparison with the nonselective steroidal antagonist RU-486 (mifepristone). PF-02367982 was found to be a potent PR antagonist with far greater selectivity over the glucocorticoid receptor than RU-486. Both PF-02367982 and RU-486 blocked progesterone-induced arborization of the rabbit endometrium in a dose-dependent manner at unbound drug exposures that were commensurate with their potencies as PR antagonists in vitro. Translation of this pharmacology to a clinically relevant system was required to bridge the pharmacological gap between nonmenstruating rabbits and humans. Thus, the pharmacokinetic (PK) and pharmacodynamic (PD) data from the rabbit were combined to predict pharmacological effects on the naturally cycling cynomolgus macaque endometrium. PF-02367982 blocked the effect of progesterone on the cynomolgus macaque endometrium to the same degree as RU-486 and at exposures predicted by the rabbit PK-PD model. With such an efficacious and superior selectivity profile to the nonselective RU-486, PF-02367982 may have significant therapeutic value in the treatment of gynecological conditions such as endometriosis.

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