Eur J Gynaecol Oncol. 2008;29(3):256-9.

Synchronous ovarian and endometrial carcinoma: a strong link to endometriosis?

Kondi-Pafiti A, Grapsa D, Liapis A, Papadias K, Kairi-Vassilatou E, Hasiakos D.

Pathology Laboratory, University of Athens, Aretaieion Hospital, Athens, Greece.

PURPOSE: To further study the clinicopathological features of synchronous ovarian and endometrial carcinomas. METHODS: We retrospectively studied all cases of synchronous ovarian and endometrial carcinomas diagnosed in our laboratory over the last 15-year period. The pathological findings were correlated with the clinical records of the patients. RESULTS: Seven cases of synchronous primary ovarian and endometrial carcinomas were retrieved. The most common presenting symptom was abnormal vaginal bleeding (5 cases, 71.4%). Five patients (71.4%) were postmenopausal and two (28.6%) were nulliparous. All seven patients had Stage I ovarian and endometrial carcinomas of endometrioid histology. Moreover, in all seven ovarian carcinomas endometriosis foci were observed, while atypical endometriosis was found in four of them. With the exception of one patient, who received adjuvant postoperative radiation, all remaining patients were treated with surgery alone. All patients were alive and free of disease at completion of the study. CONCLUSION: The correct classification of synchronous primary ovarian and endometrial carcinomas is often problematic because of the frequent confusion with their metastatic counterparts. Although the exact etiology remains unclear, endometriosis seems to be a major risk factor for their development.

Pathologe. 2008 Sep;29(5):375-7.

[Malignant mixed Müllerian tumor of the urinary bladder]

[Article in German]

Schildhaus HU, Mikuz G, Fisang C, Steiner S, Büttner R, Wardelmann E.

Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn.

True mixed epithelial-mesenchymal tumors of the urinary bladder are exceedingly rare, and only two vesical adenosarcomas have been reported to date. These tumors originated from bladder endometriosis, and malignant transformation of endometriosis has been described, with endometrioid and clear-cell carcinomas being the most common malignancies. We report an unusual case of a malignant mixed Müllerian tumor with heterologous rhabdomyoblastic differentiation, which originated in the urinary bladder of a postmenopausal woman. To the best of our knowledge, such a neoplasm has not yet been reported in the literature.

Acupunct Med. 2008 Jun;26(2):94-110.

Is there a role for acupuncture in endometriosis pain, or ‘endometrialgia’?

Lundeberg T, Lund I.

Foundation for Acupuncture and Alternative Biological Treatment Methods, Sabbatsbergs Hospital, Stockholm, Sweden.

Endometriosis is a common cause of pelvic pain in women, many of whom suffer a progression of symptoms over their menstrual life. Symptoms may include combinations of abnormal visceral sensations and emotional distress. Endometriosis pain, or ‘endometrialgia’ often has a negative influence on the ability to work, on family relationships and sense of worth. Endometrialgia is often considered to be a homogeneous sensory entity, mediated by a specialised high threshold sensory system, which extends from the periphery through the spinal cord, brain stem and thalamus to the cerebral cortex. However, multiple mechanisms have been detected in the nervous system responsible for the pain including peripheral sensitisation, phenotypic switches, central sensitisation, ectopic excitability, structural reorganisation, decreased inhibition and increased facilitation, all of which may contribute to the pain. Although the causes of endometrialgia can differ (eg inflammatory, neuropathic and functional), they share some characteristics. Endometrialgia may be evoked by a low intensity, normally innocuous stimulus (allodynia), or it may be an exaggerated and prolonged response to a noxious stimulus (hyperalgesia). The pain may also be spontaneous in the absence of any apparent peripheral stimulus. Oestrogens and prostaglandins probably play key modulatory roles in endometriosis and endometrialgia. Consequently many of the current medical treatments for the condition include oral drugs, like non-steroid anti-inflammatory drugs, contraceptives, progestogens, androgenic agents, gonadotrophin releasing hormone analogues, as well as laparoscopic surgical excision of the endometriosis lesions. However, management of pain in women with endometriosis is currently inadequate for many. Possibly acupuncture and cognitive therapy may be used as an adjunct.

Womens Health Issues. 2008 Jul-Aug;18(4):319-27.

Predictors of hysterectomy as a treatment for menstrual symptoms.

Graham M, James EL, Keleher H.

School of Health and Social Development, Deakin University, Victoria, Australia.

BACKGROUND: Hysterectomy is a common procedure in Australia; approximately 1 in 5 Australian women undergoing a hysterectomy by the age of 50 for indications such as fibroids, disorders of menstruation (including excessive or irregular menstrual bleeding), and endometriosis. However, little is known about the characteristics of women who have had the procedure or the predictors of hysterectomy as a treatment for menstrual problems. This study of 687 middle-aged Australian women suffering from menstrual symptoms aimed to identify the common health and demographic characteristics that were likely to lead to hysterectomy for the treatment of these problems. METHODS: A cross-sectional and a prospective cohort study were undertaken as a substudy of the Australian Longitudinal Study on Women’s Health (Women’s Health Australia). Women from the mid-aged cohort of the Women’s Health Australia study who identified having menstrual problems (n = 715) in the 1996 and 1998 surveys or who had undergone a hysterectomy (n = 218) during that time were recruited. A self-administered instrument was mailed to the 933 women in 2000. Data were analyzed using backward logistic regression to identify the characteristics that increased the likelihood of women undergoing hysterectomy for the treatment of menstrual problems. RESULTS: Factors that increased the likelihood of hysterectomy as a treatment for menstrual problems were varied. They included the number of menstrual symptoms experienced (odds ratio [OR], 1.63; p < .005) or conditions diagnosed (such as fibroids or excessive menstrual bleeding; OR, 2.5; p < .0005), a perception that information was available about menstrual problems (OR, 1.16; p < .001), being influenced in the decision making process to elect a treatment option (OR, 1.25; p < .025), and dissatisfaction with the other treatments tried before hysterectomy (OR, 0.63; p < .0005). CONCLUSIONS: Hysterectomy seem to be the treatment of choice for women experiencing a number of menstrual problems and less than satisfactory outcomes with other treatment options. Importantly, women appear to be making decisions based on the perception of sufficient information available about their menstrual problems, regardless of whether or not this was actually the case. Women are being influenced in their decision-making process to undergo a hysterectomy by health professionals, such as general practitioners and gynecologists.

Zhongguo Zhong Yao Za Zhi. 2008 Mar;33(6):686-90.

[Study on inhibitory effect of medicated serum of SLW on estrogen production by human endometrial cells of endometriosis]

[Article in Chinese]

Li A, Xu XY, Wang H, Chen G.

College of Pharmacy, Chongqing University of Medical Science, Chongqing 400016, China.

OBJECTIVE: To explore the mechanism of inhibitory effect of SLW on estrogen production by endometrial cells of endometriosis. METHOD: After the model of eutopic primary cultured endometrial cells of endometiosis and hysteromyoma in vitro was successfully established, the changes of steroidgenic factor-1 (SF-1), chicken ovalbumin upstream-transcription factor (COUP-TF), 17-beta-hydroxysteroid dehydrogenase 1 (17-beta-HSD1) and 17-beta-hydroxysteroid dehydrogenase 2 (17-beta-HSD2) mRNA were detected by RT-PCR before and after treatment of medicated serum of SLW. The changes of SF-1 and COUP-TF protein were also observed by western blot synchronously according to the same treatment method mentioned-above. Meanwhile ,the data of hysteromyoma group was obtained from the above experiments. RESULT: The expression of SF-1 mRNA and protein, 17-beta-HSD1 mRNA was weak, but COUP-TF mRNA and protein, 17-beta-HSD2 mRNA was remarkable in Hysteromyoma endometrium, as compared with those of endometiosis ,which was taken as control group (P<0.01). After the 48 hours’ treatment of medicated serum of 5.0, 2.5 g kg(-1) d(-1) of SLW , the expression of COUP-TF mRNA and protein, 17beta-HSD2 mRNA was found significantly increased, but SF-1 mRNA and protein, 17-beta-HSD 1 mRNA was decreased in contrast to the control group (P <0.01 or P <0.05). Although the expresson of COUP-TF mRNA and protein was increased, SF-1 protein and 17-beta-HSD1 mRNA was decreased in 1.25 g kg(-1) d(-1) medicated serum group ,compared with those of the control group (P <0.01), the low dose group had no apparent inhibitory effect on the expression of SF-1, 17-beta-HSD2 mRNA. CONCLUSION: The medicated serum of SLW could inhibit the secretion of estradiol in eutopic endometrial cells of endometiosis, and its mechanism might be associated with combined action of inhibiting expression of SF-1, 17-beta-HSD1 and up-regulating expression of COUP-TF, 17-beta-HSD2.

J Minim Invasive Gynecol. 2008 Jul-Aug;15(4):435-9.

Importance of retroperitoneal ureteric evaluation in cases of deep infiltrating endometriosis.

Seracchioli R, Mabrouk M, Manuzzi L, Guerrini M, Villa G, Montanari G, Fabbri E, Venturoli S.

Minimally Invasive Gynecological Surgery Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

STUDY OBJECTIVE: To discuss our clinical and surgical experience with 30 cases of ureteral endometriosis. DESIGN: Retrospective analysis (Canadian Task Force classification II-3). SETTING: Tertiary care university hospital. PATIENTS: Records were assessed for all patients who underwent laparoscopic surgery for deep infiltrating endometriosis (DIE) from June 2002 through June 2006. Thirty patients were laparoscopically given a diagnosis that was histologically confirmed of ureteral involvement by endometriosis. INTERVENTIONS: Laparoscopic retroperitoneal examination and management of ureteral endometriosis. MEASUREMENTS AND MAIN RESULTS: Variables assessed were: preoperative findings (patient characteristics, clinical symptoms, preoperative workup), operative details (type and site of ureteral involvement, associated endometriotic lesions, type of intervention, intraoperative complications), and postoperative follow-up (short- and long-term outcomes). We recorded details of 30 patients with a median age of 33.33 years and a median body mass index of 21.96. Symptoms reported were: none in 20 (66.7%) of 30 patients, specific in 10 (33.3%) of 30, dysuria (30%), renal angle pain (10%), hematuria (3.3%), and hydroureteronephrosis (33.3%). Ureteral endometriosis was presumptively diagnosed before surgery in 40% of patients. Ureteric involvement was on the left side in 46.7%, on the right side in 26.7%, and bilaterally in 26.7%. It was extrinsic in 86.7% and intrinsic in 13.3%. It was associated with endometriosis of homolateral uterosacral ligament in all (100%) of 30, the bladder in 50%, rectovaginal septum in 80%, ovaries in 53.3%, and bowel in 36.7%. Laparoscopic intervention was: only ureterolysis in 73.3%, segmental ureteral resection and terminoterminal anastomosis in 16.7%, and segmental ureterectomy and ureterocystoneostomy in 10%. Early postoperative complications were: fever greater than 38 degrees C requiring medical therapy for 7 days in 7 patients and 1 patient had transient urinary retention requiring catheterization that resolved without further treatment. During a mean follow-up period of 14.6 months, endometriosis recurred in 3 patients with no evidence of ureteral reinvolvement. CONCLUSION: Ureteral involvement is a silent, serious complication that must be suspected in all cases of DIE. Retroperitoneal laparoscopic isolation and inspection of both ureters helps to diagnose silent ureteral involvement. Conservative laparoscopic surgery provides a safe, feasible modality for management of ureteral endometriosis.

J Obstet Gynaecol Res. 2008 Jun;34(3):428-35.

Rectovestibular fistula as neovagina in congenital cervico-vaginal agenesis associated with imperforate anus.

Matignas AL, Delos Reyes RH.

Jose R. Reyes Memorial Medical Center, Santa Cruz, Manila.

An 18-year-old female presented with primary amenorrhea and progressive cyclic abdominal pain, which prompted emergency exploratory laparotomy. Intraoperative findings revealed absent cervix and vagina, partial bicornuate uterus, hematometra, left tubal endometriosis, ruptured left endometrioma and left renal agenesis. Left salpingectomy, left oophorocystectomy, hysterotomy, evacuation of menstrual blood and transverse loop colostomy were performed. Depo-medroxyprogesterone acetate was administered to suppress menses. On re-exploration, utero-rectovestibular fistula anastomosis was described with the distal rectovestibular fistula functioning as a neovagina. Cyclic menses occurred thereafter. Endorectal pull-through with anoplasty was performed after the fistulous tract healed. To the best of our knowledge, this is the first reported case of cervico-vaginal agenesis associated with imperforate anus and rectovestibular fistula. Early diagnosis and surgery are necessary to avoid complications such as endometriosis. The aim was to preserve fertility with conservative management.

Tidsskr Nor Laegeforen. 2008 Jun 26;128(13):1515-8.

[Surgical treatment of endometriosis]

[Article in Norwegian]

Langebrekke A, Johannessen HO, Qvigstad E.

Kvinneklinikken, Ullevål universitetssykehus, 0407 Oslo.

BACKGROUND: Endometriosis is defined as a condition with ectopic endometrial tissue outside the uterine cavity, with pain and infertility as the dominating symptoms. The disease affects about 10% of fertile women. We have described the most common manifestations of endometriosis (peritoneal, ovarian and deep endometriosis) with an emphasis on surgical treatment. MATERIAL AND METHODS: This paper is based on literature retrieved from non-systematic searches of Medline and other databases, with an emphasis on randomised and large studies, as well as our own clinical experience and international collaboration. RESULTS AND INTERPRETATION: All gynecological departments should treat peritoneal endometriosis surgically in conjunction with diagnostic laparoscopy. Medical treatment, with amenorrhoea as a goal, relieves pelvic pain, but has no beneficial effect on fertility. ovarian endometriosis should be treated surgically. Upon surgery, the pseudocapsule should be removed, possibly with ablation close to the ovarian hilus to conserve as much functional ovarian tissue as possible. Larger endometriomas- especially kissing ovaries- are often combined with deep endometriosis, and treatment in specialized hospitals should be considered. deep endometriosis must usually be treated surgically. When endometriosis affects the vagina, bowel and/or bladder, surgery is challenging, time-consuming and often involves collaboration with gastrosurgeons and/or urologists. Treatment of these difficult cases should be centralized.

Surg Obes Relat Dis. 2008 Sep-Oct;4(5):608-11. Epub 2008 Jun 30.

Incidental pathologic findings in open resectional gastric bypass specimens with routine cholecystectomy and appendectomy.

Sohn VY, Arthurs ZM, Martin MJ, Sebesta JA, Branch JB, Champeaux AL.

Department of Surgery, Madigan Army Medical Center, Tacoma, Washington 98431, USA.

BACKGROUND: Morbid obesity has become a public health epidemic in the United States. With this epidemic, the demand for surgical intervention has led to rapid growth in the field of bariatric surgery. Although various procedures exist, one of the procedures offered at our institution is resectional Roux-en-Y gastric bypass with incidental cholecystectomy and appendectomy. This procedure allows for pathologic assessment of otherwise normal viscera routinely removed as a part of the gastric bypass. The purpose of this study was to determine the incidence of abnormal findings of the extirpated, gallbladder, appendix, and distal stomach after gastric bypass surgery. METHODS: We performed a retrospective review of 427 patients undergoing Roux-en-Y at a tertiary level medical center. RESULTS: Abnormal findings were divided according to the organ. In the gastric remnant, the reported pathologic findings included chronic or active gastritis in 66, fundic gland polyps in 7, intestinal metaplasia in 3, gastric ulcers in 2, gastropathy in 2, lymphoid aggregate in 1, diverticulum in 1, a developmental cyst in 1, and leiomyoma in 1. We analyzed 311 appendixes and found the following abnormalities: fibrous obliteration of the appendiceal lumen in 76, carcinoids in 2, infarcted appendicial epiploica in 2, follicular hyperplasia in 2, and subserosal endometriosis in 1. In the gallbladder the sole abnormality, other than cholelithiasis, was an adenomyoma. Other resected findings included five Meckel’s diverticula, one bile duct adenoma, and one sigmoid diverticulum. CONCLUSION: The results of our study have shown that the resection of grossly normal and asymptomatic organs results in a very low prevalence of clinically significant incidental pathologic findings.

Am J Obstet Gynecol. 2008 Jul;199(1):e12-3.

A severe vaginal hemorrhage caused by cervical endometriosis.

Yokota N, Yoshida H, Sakakibara H, Inayama Y, Hirahara F.

Department of Obstetrics and Gynecology, Yokohama City University School of Medicine, Yokohama city, Kanagawa Prefecture, Japan.

We report a rare case in which a cystic lesion in the cervix, caused by endometriosis, resulted in a massive vaginal hemorrhage. Cervical endometriosis is relatively common and is usually considered a mild condition. However, we report a case in which a severe vaginal bleed originated from an endometrial cyst of the cervix and in which diagnosis was confused by the presence of atypical cells.

Gynecol Endocrinol. 2008 Jun;24(6):326-30.

Gelatinase A (MM-2), gelatinase B (MMP-9) and their inhibitors (TIMP 1, TIMP-2) in serum of women with endometriosis: Significant correlation between MMP-2, MMP-9 and their inhibitors without difference in levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in relation to the severity of endometriosis.

Salata IM, Stojanovic N, Cajdler-Łuba A, Lewandowski KC, Lewiński A.

Department of Endocrinology and Metabolic Diseases, The Medical University of Lodz and Polish Mother’s Memorial Hospital-Research Institute, Lodz, Poland.

Endometriosis is a highly prevalent gynecological condition, where the formation of endometriotic foci is linked with locally increased activity of matrix metalloproteinases (MMPs). In the present study, we tested the hypothesis that raised serum levels of MMPs might reflect the severity of endometriosis. We compared serum levels of MMP-2 and MMP-9, and of their tissue inhibitors TIMP-1 and TIMP-2, in infertile women, matched for age and body mass index, with either mild (stage I, END-I; n = 15) or severe endometriosis (stage IV, END-IV; n = 22). There was no difference in the concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 between the analyzed groups. There was, however, a correlation between MMP-9 and TIMP-1 for the combined group (n = 37) (r = 0.48; p = 0.0032) and in women with END-IV (r = 0.51; p = 0.0163), as well as a highly significant correlation between MMP-2 and TIMP-2 for the combined group (r = 0.69; p = 0.0001), END-I (r = 0.51; p = 0.0406) and END-IV groups (r = 0.77; p = 0.0001). There was also a significant correlation between TIMP-1 and TIMP-2 in the combined and END-IV groups (r = 0.39; p = 0.0182 and r = 0.5450; p = 0.0099, respectively). The balance between MMPs and their inhibitors is preserved in the serum of women with endometriosis, but serum concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 cannot be considered to represent a valid measure of the severity of endometriosis.

Am J Pathol. 2008 Aug;173(2):433-41. Epub 2008 Jun 26.

Cyclic adenosine 3′,5′-monophosphate response element-binding protein and CCAAT/enhancer-binding protein mediate prostaglandin E2-induced steroidogenic acute regulatory protein expression in endometriotic stromal cells.

Hsu CC, Lu CW, Huang BM, Wu MH, Tsai SJ.

Department of Physiology, National Cheng Kung University Medical College, Tainan 701, Taiwan, Republic of China.

Aberrant expression of the steroidogenic acute regulatory (StAR) protein in human endometriotic stromal cells plays an important role in the development of endometriosis. Prostaglandin E(2) (PGE(2)) is a potent inducer of StAR expression in these cells; however, the mechanisms responsible for the transcriptional regulation of StAR remain to be elucidated. Herein we report that PGE(2)-induced StAR expression is independent of the transcriptional suppressor DAX-1 but is regulated by the transcriptional activator cyclic adenosine 3′,5′-monophosphate (cAMP) response element-binding protein (CREB). A promoter activity assay revealed that the cis-element needed for the binding of the CCAAT/enhancer-binding protein (C/EBP) was critical for PGE(2)-induced StAR expression. Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells. Results from a chromatin immunoprecipitation assay demonstrated that the binding of C/EBPbeta to the StAR promoter was increased whereas CREB binding was unchanged after PGE(2) treatment. Taken together, PGE(2)-induced StAR promoter activity appears to be regulated by CREB and C/EBPbeta in a cooperative manner in ectopic human endometriotic stromal cells, providing a molecular framework for the etiology of endometriosis.

Am Fam Physician. 2008 Jun 1;77(11):1535-42.

Summary for patients in:

Am Fam Physician. 2008 Jun 1;77(11):1544.

Chronic pelvic pain in women.

Ortiz DD.

CHRISTUS Santa Rosa Family Medicine Residency Program, San Antonio, Texas 78207, USA.

The etiology of chronic pelvic pain in women is poorly understood. Although a specific diagnosis is not found in the majority of cases, some common diagnoses include endometriosis, adhesions, irritable bowel syndrome, and interstitial cystitis. The initial history and physical examination can narrow the diagnostic possibilities, guide any subsequent evaluation, and rule out malignancy or significant systemic disease. If the initial evaluation does not reveal a specific diagnosis, a limited laboratory and ultrasound evaluation can clarify the diagnosis, as well as rule out serious disease and reassure the patient. Few treatment modalities have demonstrated benefit for the symptoms of chronic pelvic pain. The evidence supports the use of oral medroxyprogesterone, goserelin, adhesiolysis for severe adhesions, and a multidisciplinary treatment approach for patients without a specific diagnosis. Less supporting evidence is available for oral analgesics, combined oral contraceptive pills, gonadotropin-releasing hormone agonists, intramuscular medroxyprogesterone, trigger point and botulinum A toxin injections, neuromodulative therapies, and hysterectomy.

Int J Gynecol Pathol. 2008 Jul;27(3):398-401.

Ovarian adenosarcoma with extensive deciduoid morphology arising in endometriosis: a case report.

Manipadam MT, Munemane A, Emmanuel P, McCluggage WG.

Department of General Pathology, Christian Medical College, Vellore-632004, Tamil Nadu, India.

A case of müllerian adenosarcoma arising in ovarian endometriosis is reported in which the whole of the mesenchymal component exhibited striking deciduoid morphology, a phenomenon that has not been previously described. The patient was not taking hormonal preparations. We discuss the differential diagnosis and the possible pathogenesis of the deciduoid stromal alteration.

Endocr J. 2008 Oct;55(5):795-810. Epub 2008 Jun 26.

Molecular and cellular mechanisms for differentiation and regeneration of the uterine endometrium.

Maruyama T, Yoshimura Y.

Department of Obstetrics and Gynecology, School of Medicine, Keio University, Yokyo, Japan.

The human endometrium undergoes cyclical changes including proliferation, differentiation, tissue breakdown, and shedding (menstruation) throughout a woman’s reproductive life. The postovulatory rise in ovarian progesterone induces profound remodeling and differentiation of the estradiol-primed endometrium. This change, termed decidualization, is crucial for embryo implantation and maintenance of the pregnancy. To date, activation and crosstalk of cAMP- and progesterone-mediated signaling pathways have emerged as key cellular events to drive integrated changes at both the transcriptome and the proteome levels. This results in the induction and maintenance of the decidual phenotype and function. Our recent series of studies highlights the critical role of SRC kinase activation (v-src sarcoma viral oncogene homolog) and STAT5 (signal transducer and activator of transcription 5) phosphorylation in decidualization. After separation of the functional layer of the differentiated endometrium that follows progesterone withdrawal, i.e., menstruation, the basal layer of the endometrium, under the influence of estradiol, regrows and initiates a unique form of angiogenesis and regenerates a new functional layer. The molecular and cellular mechanisms for this process remain elusive, mainly because of difficulties in reproducing menstrual tissue breakdown, shedding, and subsequent tissue regeneration in vitro. We have recently developed a “humanized” mouse model in which a functional human endometrium is reconstituted. It may be used as an in vivo experimental tool for the study of endometrial angiogenesis and regeneration. This model may also be used to identify and test new therapeutic strategies for endometriosis, endometrial cancer, implantation failure, and infertility related to endometrial dysfunction.

Reprod Sci. 2008 May;15(5):493-505.

DNA-binding ability of NF-kappaB is affected differently by ERalpha and ERbeta and its activation results in inhibition of estrogen responsiveness.

Guzeloglu-Kayisli O, Halis G, Taskiran S, Kayisli UA, Arici A.

Division of Reproductive Endocrinology, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520-8063, USA.

Estrogenic effects involve interactions between estrogen receptors (ERs), response elements, and nuclear proteins. It is hypothesized that interaction between ER and NF-kappa B may affect the regulation of responsive genes. Electrophoretic mobility shift assay (EMSA) was performed to assess if the interaction of ERs and NF- kappaB affect their respective DNA-binding activities, and alkaline phosphatase assay was done to evaluate estrogenic activity. EMSA revealed that ERs inhibit DNA-binding of p50 and p65, whereas p50 did not impair ER alpha binding. Stimulation with estradiol inhibited DNA binding of NF-kappaB in ERalpha-transfected endometrial stromal cells (ESCs). Moreover, activation of NF-kappaB significantly decreased estrogen responsiveness of Ishikawa cells and ERalpha-transfected ESC. Our results suggest that ERs downregulate NF-kappaB-dependent gene activation by directly preventing DNA binding. However, NF-kappaB-mediated inhibition of ER-dependent gene activation may be carried out indirectly rather than through a direct inhibition of ER-DNA binding. These findings offer new insight into the specific role of ERalpha and could eventually help in developing therapeutics for endometriosis.

Reprod Sci. 2008 Jul;15(6):543-51.

beta-HCG/LH receptor (beta-HCG/LH-R) expression in eutopic endometrium and endometriotic implants: evidence for beta-HCG sensitivity of endometriosis.

Hudelist G, Huber A, Knoefler M, Haider S, Kolbus A, Czerwenka K, Helmy S, Kubista E, Singer CF.

Division of Special Gynaecology, Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria.

BACKGROUND: Luteinizing hormone (LH) and human chorionic gonadotropin (HCG) target their receptor in gonadal and nongonadal cells to stimulate steroidogenesis and cell growth. The aim of the present study was to investigate the expression of HCG/LH-R in endometriosis to elucidate a possible impact of LH and HCG on this disease. MATERIALS AND METHODS: Analysis of HCG/LH-R protein expression in 23 paired samples of ectopic and eutopic tissue of cycling women with endometriosis and in endometrial samples from 22 healthy controls was conducted via immunofluorescence. HCG and HCG/LH-R gene expression in endometriotic lesions was confirmed by reverse-transcriptase polymerase chain reaction. RESULTS: In endometriotic implants, epithelial HCG/LH-R was found in 12/23 samples. No significant differences in HCG/LH-R levels were observed when compared with glands of uterine endometrium from the same patients or healthy controls. Messenger RNA transcripts for HCG were detected in all 12 samples, whereas HCG/LH-R mRNAs were observed in 10 of the 12 endometriotic lesions investigated. CONCLUSIONS: Although HCG/LH-R was not found to be selectively upregulated in endometriosis, the mere presence of HCG/LH-R in endometriotic tissue may suggest sensitivity of endometriosis to HCG and LH that target HCG/LH-R.

Health (London). 2008 Jul;12(3):349-67.

Endurance and contest: women’s narratives of endometriosis.

Markovic M, Manderson L, Warren N.

School of Psychology, Psychiatry and Psychological Medicine, Monash University, Victoria, Australia.

Endometriosis is an often painful medical condition in which, in response to hormones associated with the menstrual cycle, the uterine lining grows in the peritoneum and other organs, bleeding into the surrounding organs and tissues. Diagnosis is not always straightforward, and women and health professionals alike may have difficulties recognizing period pain as a sign of anomaly, considering it instead as an inevitable part of menstruation. This article describes the illness narratives of Australian women with endometriosis, drawing on data collected during a study conducted in Victoria in 2004-5. Thirty women (aged 20-78 years) from various socio-demographic backgrounds participated in in-depth interviews. We explore the influence of socio-demographic background and social and family norms on women’s illness narratives of endurance and contest. Narratives of endurance are characterized by the normalization of period pain by young women, their families and health professionals, and, with diagnosis, long-term exposure to biomedical treatments. In contrast, narratives of contest are dominated by how women’s subjective experience is challenged by doctors, their requirements for a patient-centered approach, and their desire to have access to complementary treatments.

Sichuan Da Xue Xue Bao Yi Xue Ban. 2008 May;39(3):427-9.

[Impact of NO in peritoneal fluid on sperm motility in patients with endometriosis]

[Article in Chinese]

Luo L, Tan SQ, Xu YF.

Department of Reproductive Endocrinology, West China Second Hospital, Sichuan University, Chengdu 610041, China.

OBJECTIVE: To determine the level of NO in the peritoneal fluids in patients with endometriosis and to evaluate the impact of NO on human sperm motility. METHODS: Peritoneal fluids were taken from 19 patients with Endometriosis, 16 infertile patients with Endometriosis, and 21 patients without Endometriosis (control group). The macrophages in the peritoneal fluids were segregated and cultivated. The concentrations of NO metabolin (nitrate and nitrite) were measured. Human sperms were incubated with the culture fluids to detect the motility of the sperms. RESULTS: The patients with Endometriosis had significant higher levels of NO in the peritoneal fluids than the controls (P < 0.05). The motility of sperms declined significantly in the culture fluids of infertile patients with Endometriosis compared with the fertile patients with Endometriosis and the controls (P < 0.05). CONCLUSION: Elevated NO in the peritoneal fluids in patients with endometriosis may play a role in the pathogeneses of Endometriosis-associated infertility.

Sichuan Da Xue Xue Bao Yi Xue Ban. 2008 May;39(3):424-6, 437.

[Impact of progesterone in peritoneal fluid on sperm motility in infertile patients with endometriosis]

[Article in Chinese]

Xu YF, Tan SQ, Luo L.

Department of Reproductive Endocrinology, West China Second Hospital, Sichuan University, Chengdu 610041, China.

OBJECTIVE: To evaluate the impact of progesterone in the peritoneal fluid on human sperm motility in the infertile patients with endometriosis. METHODS: Peritoneal fluids were collected from 41 patients by laparoscopy, of which 17 were infertile patients with endometriosis, 11 were fertile patients with endometriosis and 13 were fertile controls. The concentrations of progesterone in the peritoneal fluids were measured by the immulyze-enzyme amplified luminescence system. After 4 h of incubation in vitro with the collected peritoneal fluids, sperm motility was assessed by the computer-assisted analyzer (CASA). RESULTS: The concentrations of progesterone in the peritoneal fluids in the patients (infertile patients with endometriosis, fertile patients with endometriosis and the fertile controls) did not differ significantly (P > 0.05) in the proliferate phase. The sperms incubated with the peritoneal fluids from the patients with endometriosis had significant lower sperm motion parameters (A, VCL, VSL, VAP, ALH) than those of the fertile controls (P < 0.05). Although the sperm motility incubated with the peritoneal fluids from the patients with endometriosis was enhanced by the exogenous progesterone, no significant correlation was established between the concentrations of progesterone in the peritoneal fluids and the sperm motility (P > 0.05). CONCLUSION: The peritoneal fluids of infertile patients with endometriosis inhibit the sperm motility. The inhibition is not associated with the concentrations of progesterone in the peritoneal fluids. However, the sperm motility can be enhanced by adding exogenous progesterone to the peritoneal fluids.

Ann N Y Acad Sci. 2008;1135:185-95.

Dysmenorrhea in adolescents.

Harel Z.

Division of Adolescent Medicine, Hasbro Children’s Hospital, 593 Eddy Street, Providence, RI 02903, USA.

Dysmenorrhea is the most common gynecologic complaint among adolescent females. Dysmenorrhea in adolescents is usually primary, and is associated with normal ovulatory cycles and with no pelvic pathology. In approximately 10% of adolescents with severe dysmenorrheic symptoms, pelvic abnormalities such as endometriosis or uterine anomalies may be found. Potent prostaglandins and leukotrienes play an important role in generating the symptoms of dysmenorrhea. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common pharmacologic treatment for dysmenorrhea. A loading dose of NSAIDs (typically twice the regular dose) should be used as initial treatment for dysmenorrhea in adolescents, followed by a regular dose until symptoms abate. Adolescents with symptoms that do not respond to treatment with NSAIDs for three menstrual periods should be offered hormonal treatment such as combined estrogen/progestin oral contraceptive pills for three menstrual cycles. Adolescents with dysmenorrhea who do not respond to this treatment should be evaluated for secondary causes of dysmenorrhea. The adolescent care provider’s role is to explain the pathophysiology of dysmenorrhea to every adolescent female, address any concern that the patient has about her menstrual period, and review effective treatment options for dysmenorrhea with the patient.

Expert Rev Med Devices. 2008 Jul;5(4):437-45.

Levonorgestrel-releasing intrauterine system: uses and controversies.

Bahamondes L, Bahamondes MV, Monteiro I.

Department of Obstetrics and Gynecology, School of Medicine, University of Campinas, Caixa Postal 6181, Campinas, SP, Brazil.

This article provides a perspective on the use of the levonorgestrel-releasing intrauterine system as a contraceptive method and as therapy in different situations, as well as presenting the corresponding controversies and unresolved issues. All studies have reported high contraceptive efficacy, an improvement in menstrual blood loss in women with idiopathic menorrhagia, menorrhagia due to thrombophilic diseases and fibroids, and excellent endometrial protection during postmenopausal estrogen therapy. Moreover, the device is able to reduce pelvic pain and dysmenorrhea as well as improve the staging of endometriosis and adenomyosis, and to control, albeit partially, endometrial hyperplasia. The expectation is that in years to come the number of hysterectomies and female sterilizations will fall due to increased use of the device, including use by patients with endometriosis and HIV-positive women. It would also be desirable to develop a smaller device for postmenopausal women and nulligravidas.

Cir Esp. 2008 Jun;83(6):334-5.

[Appendix endometriosis as a cause of recurring chronic pain in the right iliac fossa]

[Article in Spanish]

Gibert-Gerez J, Martínez-Ramos D, Alfaro-Ferreres L, Nomdedéu Guinot J.

Can J Urol. 2008 Jun;15(3):4097-100.

Asymptomatic rectal and bladder endometriosis: a case for robotic-assisted surgery.

Chammas MF Jr, Kim FJ, Barbarino A, Hubert N, Feuillu B, Coissard A, Hubert J.

Denver Health Medical Center, University of Colorado Health Sciences Center, Denver, Colorado 80204, USA.

OBJECTIVES: To evaluate the feasibility and safety of robot-assisted laparoscopic partial cystectomy for the treatment of rectal and bladder endometriosis. MATERIALS AND METHODS: A 23 year-old female with history of infertility and pelvic pain was found to have a 4 cm bladder mass and rectal nodule on pelvic ultrasonography. Patient denied any other genitourinary symptoms. Cystoscopy and bladder mass biopsy revealed endometriosis. After failure to suppressive hormonal medical therapy a partial cystectomy and resection of a rectal lesion was performed with robotic assistance (da Vinci). The procedure included excision of an ovarian cyst and several peritoneal endometrioid implants. RESULTS: Robotic-assisted (da Vinci) partial cystectomy with concomitant excision of endometrial nodules from the rectum and ovarian cyst was performed in 185 min. The rectal lesion was excised and primary closure of the rectum was performed. Patient had an uneventful postoperative course and hospital stay. Oral intake was started on postoperative day 1 and follow-up imaging revealed no bladder extravasation or fistula formation. The patient became pregnant 2 years later with “in vitro” fertilization procedure. CONCLUSIONS: Robotic-assisted laparoscopic partial cystectomy with excision of rectal nodules for endometriosis can be safely performed.

J Obstet Gynaecol. 2008 Apr;28(3):360.

Clostridium perfringens infection following endometrial ablation.

Halawa S, Kassab A, Fox R.

Division of Women’s and Children’s Health, Taunton and Somerset Hospital, Taunton, UK.

J Obstet Gynaecol. 2008 Apr;28(3):354-5.

Comment in:

J Obstet Gynaecol. 2008 Apr;28(3):261.

An unusual case of catamenial pneumothorax.

Garg V, McKenzie Gray B.

Princess Royal Hospital, Haywards Heath, UK.

Gynecol Endocrinol. 2008 May;24(5):235-6.

Non-contraceptive use of hormonal contraceptives.

Schindler AE.

Acta Radiol. 2008 Jul;49(6):700-9.

Magnetic resonance evaluation of adnexal masses.

Guerra A, Cunha TM, Félix A.

Department of Radiology, Hospital Pulido Valente, Lisbon, Portugal.

BACKGROUND: Accurate evaluation of adnexal masses allows correct surgical procedure, avoiding unnecessary surgery. PURPOSE: To evaluate the accuracy of magnetic resonance imaging (MRI) in the diagnosis of malignancy of adnexal lesions. MATERIAL AND METHODS: We retrospectively reviewed the pelvic MRI scans of 161 patients with 199 surgically confirmed adnexal masses, between November 1998 and June 2005. The criteria for adnexal malignancy were contrast-enhanced solid lesions, contrast-enhanced solid components in mixed lesions (except those with low-signal-intensity solid components on T2-weighted imaging [T2WI]), contrast-enhanced papillary projections in cystic lesions (except those with low-signal-intensity papillary projections on T2WI), or septal thickness >or=3 mm. Ascites, peritoneal metastasis, and pelvic adenopathy were also regarded as criteria for malignancy. RESULTS: On MRI evaluation, 97 adnexal lesions were malignant and 102 were non-malignant. Thirty-two percent of patients with ascites had benign lesions. Histopathologic evaluation of the adnexal lesions showed that 83 were malignant (true positives), 100 were non-malignant (true negatives), and seven were uncertain malignant potential tumors; two were false negative and seven were false positive. The MRI sensitivity and specificity for malignancy were 98% and 93%, respectively. MRI reached an accuracy of 95%, with a positive predictive value of 0.92 and a negative predictive value of 0.98 for malignant adnexal lesions. The kappa coefficient was 0.906, indicating almost perfect agreement between MRI and histological results. CONCLUSION: MRI is an accurate method for evaluating the malignancy of adnexal lesions.

Ceska Gynekol. 2008 Apr;73(2):125-7.

[The endometriosis combined treatment results of the Department of Gynecology and Minimally Invasive Therapy, Na Homolce Hospital, Prague in six years period 2001–2007]

[Article in Czech]

Pelísek L, Kempe V, Kolrusová M, Struppl D.

Oddelení gynekologie i minimálne invazivní chirurgie, Nemocnice Na Homolce, Praha.

OBJECTIVE: The endometriosis combined treatment optimisation on the basis of own results. DESIGN: The retrospective clinical study. DEPARTMENT: Department of Gynecology and Minimally Invasive Therapy, Na Homolce Hospital Prague. METHODS: The retrospective analysis of the endometriosis treatment results on the basis of subjective severity and the inspection laparoscopy objective determination including work-up and imaging examinations. RESULTS: Out of 586 patients, who underwent endometriosis combined (surgical and medicamentous) treatment, there were 91% of patients with no subjective severity with normal inspection laparoscopy determination in area of lesser pelvis. CONCLUSION: 91% of treatment success entitles us to consider that our method of the endometriosis treatment is an option for future. We plan a long term monitoring of patients after restore to health within a period of years and percentage of pregnancy success, which we monitored alongside patients with the deep-infiltrating endometriosis.

Eur J Obstet Gynecol Reprod Biol. 2008 Jul;139(1):1-2. Epub 2008 Jun 18.

Editors’ highlights.

Drife J, Künzel W.

Fertil Steril. 2008 Nov;90(5):2004.e19-21. Epub 2008 Jun 20.

Ovarian response in women undergoing ovarian stimulation after myomectomy.

Browne H, McCarthy-Keith D, Stegmann B, Spies J, Armstrong A.

Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

OBJECTIVE: To examine ovarian response in infertile women undergoing ovarian stimulation after abdominal myomectomy. DESIGN: Case report. SETTING: Academic medical research center. PATIENT(S): Four infertile women with known fibroids who had a failed assisted reproductive technology (ART) cycle followed by an abdominal myomectomy. INTERVENTION(S): Infertile women with known fibroids who had a failed ART cycle, from January 2000 to December 2006, followed by an abdominal myomectomy and a subsequent ART cycle. MAIN OUTCOME MEASURE(S): Ovarian function before (baseline) and after myomectomy was assessed by age, day 3 and day 10 FSH levels, days of stimulation, total gonadotropins used, peak E(2) level, the number of oocytes retrieved and embryos obtained, the number of high-grade embryos, and pregnancy outcome. RESULT(S): The mean age was 35 and 36 years before and after myomectomy, respectively. All subjects had uterine factor infertility. Two of these women also had tubal factor infertility, and one had endometriosis and male factor infertility. There was no difference in ovarian response before and after myomectomy. CONCLUSION(S): As expected, abdominal myomectomy did not adversely affect ovarian response in infertile women undergoing ovarian stimulation after a failed ART cycle. Larger randomized prospective studies are needed to accurately assess whether myomectomy has a negative impact on ovarian response.

J Assist Reprod Genet. 2008 Jun;25(6):239-44. Epub 2008 Jun 19.

The frequency of ovulation from the affected ovary decreases following laparoscopic cystectomy in infertile women with unilateral endometrioma during a natural cycle.

Horikawa T, Nakagawa K, Ohgi S, Kojima R, Nakashima A, Ito M, Takahashi Y, Saito H.

Department of Perinatal Medicine and Maternal Care, National Center for Child Health and Development, Okura, Setagaya, Tokyo, Japan.

PURPOSE: To evaluate the cystectomy-induced damage on the follicular growth and ovulation of an affected ovary during natural cycles. METHODS: Twenty-eight infertile patients with unilateral ovarian endometriomas who underwent laparoscopic cystectomy were retrospectively evaluated. The ovulation rate of an affected ovary during natural cycles was compared before and after cystectomy in each patient, and it was also determined if ovulation from the affected ovaries resulted in pregnancy. RESULTS: After surgery, the ovulation rate was significantly lower than that before cystectomy (16.9 +/- 4.5% vs. 34.4 +/- 6.6%, P = 0.013). After surgery, 14 pregnancies were achieved without IVF treatment, and only 2 of them (14.3%) were achieved from an operated-side ovary. However, the pregnancy rate per ovulatory cycle of the operated-side ovary was not different from that of the intact ovary (8.8% vs. 5.8%, P = 0.750). CONCLUSIONS: Laparoscopic cystectomy is an invasive treatment in that it reduces the frequency of ovulation; however the pregnancy rate per ovulation did not deteriorate.

Gynecol Obstet Invest. 2008;66(3):169-77. Epub 2008 Jun 19.

Risk factors for dysmenorrhea and its severity in women with ovarian endometriomas.

Liu X, Yuan L, Wang Y, Shen F, Guo SW.

Department of Gynecology, Shanghai OB/GYN Hospital, Shanghai Medical School, Fudan University, Shanghai, PR China.

OBJECTIVE: To identify factors associated with the risk of developing dysmenorrhea or the severity of dysmenorrhea in women with surgically confirmed ovarian endometriomas. STUDY DESIGN: 710 patients with surgically diagnosed ovarian endometriomas were interviewed and their charts read. Fourteen factors were considered. Among the 710 patients, 376 patients had major complaint of dysmenorrhea and were evaluated to identify factors associated with the severity of dysmenorrhea. RESULTS: The logistic regression model identified younger age at surgery, previous medication use, presence of adhesion, and presence of adenomyosis as risk factors for dysmenorrhea. For the severity of dysmenorrhea, the presence of adenomyosis was consistently and robustly identified by several statistical models with rather different assumptions as the factor associated with severity. The rAFS stage was also associated with the severity, but the association may be explained by the presence of adenomyosis. CONCLUSION: The presence of adenomyosis has been consistently identified as a risk factor for both dysmenorrhea and its severity. Younger age at surgery, presence of adhesion, and previous use of endometriosis-related medication are additional risk factors for dysmenorrhea. For the severity of dysmenorrhea, there are other factors than the presence of adenomyosis that may influence the severity of dysmenorrhea. Copyright 2008 S. Karger AG, Basel.

Exp Clin Endocrinol Diabetes. 2008 Jul;116(7):371-84. Epub 2008 Jun 17.

Transcriptome studies of bovine endometrium reveal molecular profiles characteristic for specific stages of estrous cycle and early pregnancy.

Bauersachs S, Mitko K, Ulbrich SE, Blum H, Wolf E.

Laboratory for Functional Genome Analysis, Gene Center, LMU Munich, Munich, Germany.

The endometrium undergoes marked functional changes during estrous cycle and pregnancy. As the adjacent environment of the conceptus, it represents the maternal interface for embryo-maternal communication, which is essential to maintain pregnancy. Transcriptome studies provide the unique opportunity to assess molecular profiles changing in response to endocrine or metabolic stimuli or to embryonic pregnancy recognition signals. Here we review the current state of transcriptome profiling techniques and the results of a series of transciptome studies comparing bovine endometrium samples during the estrous cycle or endometrium samples from pregnant vs. non-pregnant animals. These studies revealed specific mRNA profiles which are characteristic for the functional status of the endometrium. Transcriptome studies of endometrial samples recovered during the pre-attachment period identified many interferon-stimulated genes, genes that are possibly involved in embryo-maternal immune modulation ( C1S, C1R, C4, SERPING1, UTMP, CD81, IFITM1, BST2), as well as genes affecting cell adhesion ( AGRN, CD81, LGALS3BP, LGALS9, GPLD1, MFGE8, and TGM2) and remodeling of the endometrium ( CLDN4, MEP1B, LGMN, MMP19, TIMP2, TGM2, MET, and EPSTI1). The results of these transcriptome studies were compared to those of similar microarray analyses in human, mouse and Rhesus monkey to identify similarities in endometrial biology between mammalian species and species-specific differences. Future studies will cover dynamic transcriptome changes between different stages of early pregnancy, the relationship between metabolic problems in dairy cows and the functionality of reproductive tissues as well as endometrium transcriptome profiles in recipients of somatic cell nuclear transfer embryos.

Minerva Ginecol. 2008 Aug;60(4):323-30.

Laparoscopic surgery in endometriosis.

Eltabbakh GH, Bower NA.

Lake Champlain Gynecologic Oncology, South Burlington, Vermont, USA.

Endometriosis (the presence of endometrial glands and stroma outside of the uterine cavity) is a common gynecologic problem affecting 10% of women in the general population, 40% of women with infertility and 60% of women with chronic pelvic pain. Laparoscopy has revolutionized management of women with endometriosis. Diagnosis of endometriosis depends on visualization of endometriotic lesions and histologic confirmation. Endometriotic implants have a multitude of appearances: powder burns, red, blue-black, yellow, white, clear vesicular and peritoneal windows. Diagnostic laparoscopy is often combined with operative procedures to treat manifestations and symptoms of endometriosis. This often includes removal or laser vaporization of endometriotic implants, lysis of adhesions, restoration of normal anatomy and removal or fulguration of ovarian endometriomas (conservative surgery). Severe incapacitating endometriosis, recurrent endometriosis following conservative surgery and symptomatic endometriosis in women not desiring more children is often treated by laparoscopic unilateral or bilateral salpingo-oophorectomy or laparoscopically-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy (radical surgery). Endometriosis affecting the appendix, ureters, bladder wall and rectosigmoid colon could be treated with laparoscopic appendectomy, excision of endometriotic implants or laparoscopic colectomy and anastomosis, respectively. Hydrodis-section and use of CO2 super pulsed laser aid in removal of adherent endometriotic implants without damage to normal underlying structures. Robotic-assisted laparoscopic surgery promises to provide advantages in the management of women with severe endometriosis secondary to 3-dimensional visualization, decreasing surgeon’s fatigue and hand tremors and improving surgical precision.

J Clin Endocrinol Metab. 2008 Sep;93(9):3532-40. Epub 2008 Jun 17.

Extracellularly signal-regulated kinase activity in the human endometrium: possible roles in the pathogenesis of endometriosis.

Murk W, Atabekoglu CS, Cakmak H, Heper A, Ensari A, Kayisli UA, Arici A.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8063, USA.

CONTEXT: Endometriosis is an estrogen-dependent disease characterized by the presence of endometrial tissue outside of the uterine cavity, causing pelvic pain and infertility in 10% of reproductive-aged women. It is unclear why ectopic endometrium remains viable in only a subset of women. ERK1/2 plays key intracellular roles in activating cellular survival and differentiation processes. OBJECTIVE: We sought to determine ERK1/2 activity in patients with endometriosis and its possible roles in regulating endometrial cell survival. DESIGN: ERK1/2 phosphorylation and expression throughout the menstrual cycle were evaluated in vivo in normal and endometriotic human endometrium, and in vitro techniques assessed the steroidal regulation of ERK1/2 and its effect on endometrial cell survival. RESULTS: Total ERK1/2 remained constant in normal and endometriotic endometrium throughout the menstrual cycle. Phospho-ERK1/2 was high in the late proliferative and secretory phases in normal endometrium (P < 0.05). In endometriotic glandular cells, there was no cyclical variation in phospho-ERK1/2. In endometriotic stromal cells, there was also a reduction in phospho-ERK1/2 variation, with higher levels in the early-mid secretory phase (P < 0.05). In cultured endometrial stromal cells (ESCs), estrogen plus progesterone increased ERK1/2 phosphorylation within 15 min (P < 0.05). Although estrogen alone did not induce ERK1/2 phosphorylation in normal ESCs, there was a significant response to estrogen in ESCs isolated from eutopic endometriotic endometrium (P < 0.05). ERK1/2 inhibition in ESCs reduced proliferation and increased apoptosis (P < 0.05). CONCLUSION: Abnormally high levels of ERK1/2 activity may be involved in endometriosis, possibly by stimulating endometrial cell survival.

J Clin Endocrinol Metab. 2008 Sep;93(9):3471-7. Epub 2008 Jun 17.

Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: potential relevance to the pathogenesis of endometriosis.

Bukulmez O, Hardy DB, Carr BR, Auchus RJ, Toloubeydokhti T, Word RA, Mendelson CR.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, Florida 32610-0294, USA.

CONTEXT: Up-regulation of aromatase expression in endometrial cells disseminated into the peritoneal cavity may enhance their survival via local estrogen synthesis, which may lead to endometriosis. The factors that mediate induction of aromatase in the endometrium are not well defined, but increased expression of steroidogenic factor (SF)-1 may play a role. OBJECTIVE: The objective of the study was to determine whether androstenedione (A4), the predominant sex steroid in peritoneal fluid, regulates endometrial aromatase expression. DESIGN: This was a cell/tissue culture study. SETTING: The study was conducted at an academic center. METHODS: Quantitative real-time PCR, HPLC, and chromatin immunoprecipitation were used in this study. RESULTS: Treatment of cultured human endometrial explants and stromal cells with A4 (10 nm) significantly up-regulated expression of aromatase mRNA transcripts containing exon IIa at their 5′-ends. In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1. In HES cells, tritiated A4 was metabolized to estradiol, testosterone (T), dihydrotestosterone, and androstanediol. Both estradiol and T, but not nonaromatizable androgens, up-regulated aromatase and SF-1 mRNA in HES cells. Chromatin immunoprecipitation revealed that A4 enhanced recruitment of SF-1 to its response element (-136 bp) upstream of CYP19 exon IIa. This, together with the findings that both estrogen receptor antagonist, ICI 182,780, and aromatase inhibitor, fadrozole, suppressed A4 and T induction of aromatase and SF-1 mRNA, indicates that the inductive effects of A4 and T are mediated by their conversion to estrogens. CONCLUSIONS: Exposure of endometrial cells to A4 may enhance CYP19 gene expression through its aromatization to estrogens.

Sci Total Environ. 2008 Sep 1;402(2-3):171-5. Epub 2008 Jun 16.

A case-control study of the association between urinary cadmium concentration and endometriosis in infertile Japanese women.

Itoh H, Iwasaki M, Nakajima Y, Endo Y, Hanaoka T, Sasaki H, Tanaka T, Yang B, Tsugane S.

Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Cadmium may act like an estrogen and be a potential risk factor for estrogen-related diseases such as breast cancer and endometriosis. Here, we tested the hypothesis that higher cadmium exposure is associated with endometriosis among infertile Japanese women in a hospital-based case-control study. We recruited consecutive female patients aged 20-45 years who had complained of infertility and presented to a university hospital in Tokyo. The subjects were interviewed and provided a urine sample prior to a laparoscopic diagnosis of endometriosis between January 2000 and December 2001. The severity of endometriosis was then dichotomized into controls (stage 0 and I) and cases (stage II-IV). We finally measured urinary total cadmium concentration in 54 cases and 74 controls as a biomarker of long-term cumulative exposure. Odds ratios were adjusted for average menstrual cycle length, body-mass index and smoking status using unconditional logistic regression. Results showed no association between endometriosis and urinary cadmium concentration. Medians (interquartile ranges) of urinary cadmium concentration in cases and controls were 0.53 (0.40-0.73) and 0.54 (0.34-0.76) microg/g creatinine, respectively (P for difference=0.88). Adjusted odds ratio (95% confidence interval) for the highest versus lowest tertile of urinary creatinine-adjusted cadmium concentration was 0.86 (0.30 to 2.49, P for trend=0.79). Our results do not support the hypothesis that higher urinary cadmium concentration is associated with the risk of endometriosis.

Hum Reprod. 2008 Sep;23(9):2017-23. Epub 2008 Jun 12.

Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial.

    Koninckx PR, Craessaerts M, Timmerman D, Cornillie F, Kennedy S.


    Department of Obstetrics and Gynaecology, UZ Gasthuisberg, Katholieke Universiteit Leuven, B3000 Leuven, Belgium.


    BACKGROUND: Endometriosis is associated with an inflammatory response. Hence infliximab, an anti-TNF-alpha monoclonal antibody, might relieve pain. METHODS: A randomized placebo-controlled trial was designed with 21 women with severe pain and a rectovaginal nodule of at least 1 cm. After 1 month of observation, three infusions of infliximab (5 mg/kg) or placebo were given. Surgery was performed 3 months later and follow-up continued for 6 months. The primary end-point was pain (dysmenorrhea, deep dyspareunia and non-menstrual pain) rated at each visit by the clinician and on a daily basis by the patient who in addition scored pain by visual analog pain scale and analgesia intake. Secondary end-points included the volume of the endometriotic nodule, pelvic tenderness and the visual appearance of endometriotic lesions at laparoscopy. RESULTS: Pain severity decreased during the treatment by 30% in both the placebo (P < 0.001) and infliximab groups (P < 0.001). However, no effect of infliximab was observed for any of the outcome measures. After surgery, pain scores decreased in both groups to less than 20% of the initial value. CONCLUSIONS: Infliximab appears not to affect pain associated with deep endometriosis. Treatment is associated with an important placebo effect. After surgery, pain decreases to less than 20%. Trials registration number NCT00604864.

Fertil Steril. 2008 Nov;90(5):2004.e7-9. Epub 2008 Jun 16.

Persistent bilateral ureteral obstruction secondary to endometriosis despite treatment with an aromatase inhibitor.

Bohrer J, Chen CC, Falcone T.

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44195, USA.

OBJECTIVE: To present a case demonstrating lack of efficacy of an aromatase inhibitor in treating ureteral endometriosis. DESIGN: Case report. SETTING: A tertiary-care hospital. PATIENT(S): A 47-year-old woman with severe ureteral endometriosis. INTERVENTION(S): Anastrozole 1 mg daily for 15 months. MAIN OUTCOME MEASURE(S): Renal function. RESULT(S): Despite medical management with anastrozole, our patient continued to have worsening renal function and subsequently required surgical intervention. CONCLUSION(S): Anastrozole was ineffective at preventing deterioration of renal function in this patient.

Fertil Steril. 2008 Dec;90(6):2073-9. Epub 2008 Jun 13.

Neutrophil-to-lymphocyte ratio as an adjunct to CA-125 for the diagnosis of endometriosis.

Cho S, Cho H, Nam A, Kim HY, Choi YS, Park KH, Cho DJ, Lee BS.

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

OBJECTIVE: To investigate the clinical value of differential white blood cell counts and neutrophil-to-lymphocyte ratio (NLR), by themselves or as adjunct to CA-125, in the diagnosis of endometriosis. DESIGN: Retrospective study. SETTING: University Medical Center. PATIENT(S): Two hundred thirty-one patients with endometriosis, 145 patients with benign ovarian tumors, and 384 healthy controls participated in this study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Sensitivities and specificities of differential white blood cell (WBC) counts, NLR, serum CA-125, and the combined marker (NLR and serum CA-125) were evaluated by receiver-operating characteristic (ROC) analysis. RESULT(S): The mean NLR and the combined marker in patients with endometriosis were significantly higher than those in patients without endometriosis. The NLR was able to discriminate patients with endometriosis from those with benign ovarian tumors and from healthy controls, and 25 of the 38 endometriosis patients (65.8%) with minimal-to-mild disease exceeded the cutoff value. The combined marker had a sensitivity of 69.3% and specificity of 83.9% with a cutoff value of 55.7, showing 13.5% increase in sensitivity but 8.9% decrease in specificity when compared with serum CA-125 at a cutoff level of 35 IU/mL. The elevated combined marker detected 16 patients with endometriosis (42.1%) with minimal-to-mild disease, whereas only 10 patients (26.3%) had their serum CA-125 levels at more than 35 IU/mL. CONCLUSION(S): Measurement of NLR and the combined marker may be used as simple and easily obtained diagnostic markers for endometriosis.

Am J Obstet Gynecol. 2008 Nov;199(5):486.e1-486.e10. Epub 2008 Jun 13.

Immunoreactivity of progesterone receptor isoform B and nuclear factor kappa-B as biomarkers for recurrence of ovarian endometriomas.

Shen F, Wang Y, Lu Y, Yuan L, Liu X, Guo SW.

Department of Gynecology, Shanghai OB/GYN Hospital, and Department of Gynecology and Obstetrics, Fudan University, Shanghai Medical School, Shanghai, China.

OBJECTIVE: This study was undertaken to evaluate the immunoreactivity of progesterone receptor isoform B and nuclear factor kappa-B p65 subunit in ovarian endometrioma tissue samples harvested at the time of surgery and their relationship with the recurrence risk. STUDY DESIGN: One hundred nine patients were selected; 53 of them had recurrence within 30 months after surgery, whereas the other 56 had not had recurrence at least 32 months after surgery. For each patient, host and clinical information was also collected. The patients’ archived, formalin-fixed, paraffin-embedded tissue blocks were retrieved, subjected to immunohistochemical staining of progesterone receptor isoform B and nuclear factor kappa-B p65 subunit, and were scored and compared. RESULTS: Increased nuclear factor kappa-B activation and decreased progesterone receptor isoform B immunoreactivity in ovarian endometriomas were 2 predominant factors in predicting recurrence. The classification tree method based on these 2 yielded a sensitivity of 86.6% and a specificity of 82.1%. CONCLUSION: Nuclear factor kappa-B activation/p65 and progesterone receptor isoform B immunoreactivity in ovarian endometrioma jointly constitutes a good biomarker for recurrence. The close relationship between nuclear factor kappa-B activation/p65 subunit and progesterone receptor isoform B immunoreactivity strongly suggests their roles involved in recurrence and may thus be excellent therapeutic targets to prevent recurrence. Our finding supports the notion that there are identifiable molecular genetic differences intrinsic to ovarian endometriomas that confer recurrence risk differential.

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