J Clin Endocrinol Metab. 2009 Feb;94(2):545-51. Epub 2008 Nov 25.

Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix.

Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP.

Neurocrine Biosciences Inc., 12780 El Camino Real, San Diego, California 92130, USA. sstruthers@neurocrine.com

CONTEXT: Parenteral administration of peptide GnRH analogs is widely employed for treatment of endometriosis and fibroids and in assisted-reproductive therapy protocols. Elagolix is a novel, orally available nonpeptide GnRH antagonist. OBJECTIVE: Our objective was to evaluate the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single-dose and 7-d elagolix administration to healthy premenopausal women. DESIGN: This was a first-in-human, double-blind, placebo-controlled, single- and multiple-dose study with sequential dose escalation. PARTICIPANTS: Fifty-five healthy, regularly cycling premenopausal women participated. INTERVENTIONS: Subjects were administered a single oral dose of 25-400 mg or placebo. In a second arm of the study, subjects received placebo or 50, 100, or 200 mg once daily or 100 mg twice daily for 7 d. Treatment was initiated on d 7 (+/-1) after onset of menses. MAIN OUTCOME MEASURES: Safety, tolerability, pharmacokinetics, and serum LH, FSH, and estradiol concentrations were assessed. RESULTS: Elagolix was well tolerated and rapidly bioavailable after oral administration. Serum gonadotropins declined rapidly. Estradiol was suppressed by 24 h in subjects receiving at least 50 mg/d. Daily (50-200 mg) or twice-daily (100 mg) administration for 7 d maintained low estradiol levels (17 +/- 3 to 68 +/- 46 pg/ml) in most subjects during late follicular phase. Effects of the compound were rapidly reversed after discontinuation. CONCLUSIONS: Oral administration of a nonpeptide GnRH antagonist, elagolix, suppressed the reproductive endocrine axis in healthy premenopausal women. These results suggest that elagolix may enable dose-related pituitary and gonadal suppression in premenopausal women as part of treatment strategies for reproductive hormone-dependent disease states.

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Chemosphere. 2009 Feb;74(7):944-9. Epub 2008 Nov 22.

Serum dioxins, polychlorinated biphenyls, and endometriosis: a case-control study in Atlanta.

Niskar AS, Needham LL, Rubin C, Turner WE, Martin CA, Patterson DG Jr, Hasty L, Wong LY, Marcus M.

Division of Environmental Hazards and Health Effects, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA. asniskar@gmail.com

Endometriosis among women of reproductive age can result in pain and infertility. The objectives of this study were to test if there is a relation between endometriosis and serum dioxin concentrations as expressed by total toxic equivalence and serum total polychlorinated biphenyl concentrations among women patients at one Atlanta reproductive medicine clinic during 1998-1999; a secondary objective was to provide exposure data for individual congeners of these chemicals and 1,1-dichloro-2,2-bis(4-chlorophenyl)ethane (p,p’-DDE) in women in Atlanta. Laparoscopy including biopsy and visualization of the peritoneal cavity, ovaries, outside of the fallopian tubes and uterus confirmed all endometriosis cases (n=60) and confirmed 30 controls without endometriosis. Other controls had an infertile partner (n=27) or ovulation problems (n=7) with no signs or symptoms of endometriosis. All serum samples were analyzed at the U.S. Centers for Disease Control and Prevention in 2003. Statistical analyses included Fisher’s exact chi-square tests and logistic regression. Models were presented for the full study sample and for the subset that included all cases (n=60) and only controls (n=30) with surgical confirmation of disease-free status. Serum concentrations (lipid-adjusted and non lipid-adjusted) of analyzed exposure measures were low and similar for cases and controls and did not explain endometriosis in the study population.

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Placenta. 2009 Feb;30(2):111-23. Epub 2008 Nov 22.

Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium.

Haider S, Knöfler M.

Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.

The cytokine tumour necrosis factor alpha (TNF) is a well known member of the TNF superfamily consisting of at least 18 ligands and 29 different receptors involved in numerous cellular processes. TNF signals through two distinct receptors TNFR1 and TNFR2 thereby controlling expression of cytokines, immune receptors, proteases, growth factors and cell cycle genes which in turn regulate inflammation, survival, apoptosis, cell migration, proliferation and differentiation. Since expression of TNF was discovered in amnion and placenta many studies demonstrated the presence of the cytokine and its receptors in the diverse human reproductive tissues. Whereas TNF has been implicated in ovulation, corpus luteum formation and luteolysis, this review focuses on the functions of TNF in human placental, endometrial and decidual cell types of normal tissues and also discusses its role in endometrial and gestational diseases. Physiological levels of the cytokine could be important for balancing cell fusion and apoptotic shedding of villous trophoblasts and to limit trophoblast invasion into maternal decidua. Regulation of the TNF/TNFR system by steroid hormones also suggests a role in uterine function including menstrual cycle-dependent destruction and regeneration of endometrial tissue. Aberrant levels of TNF, however, are associated with diverse reproductive diseases such as amniotic infections, recurrent spontaneous abortions, preeclampsia, preterm labour or endometriosis. Hence, concentrations, receptor distribution and length of stimulation determine whether TNF has beneficial or adverse effects on female reproduction and pregnancy.

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Arch Gynecol Obstet. 2009 Jun;279(6):891-5. Epub 2008 Nov 21.

Cytokine and immune cell levels in peritoneal fluid and peripheral blood of women with early- and late-staged endometriosis.

Hassa H, Tanir HM, Tekin B, Kirilmaz SD, Sahin Mutlu F.

Department of Obstetrics and Gynecology, Eskisehir Osmangazi University School of Medicine, Turkey.

OBJECTIVE: To investigate the level of cytokines and immune cells in the peripheral blood (PB) and peritoneal fluid (PF) of different stages of endometriosis. METHODS: A prospective study was conducted to include 97 women with (n 60) and without (n 37) histopathologically confirmed endometriosis. Based on rASRM classification, stage I/II and stage III/IV were categorized as early-and late-staged endometriosis. Prior to surgery, 10 ml of blood was withdrawn from antecubital vein and serum was obtained. Aliquots were made and stored at -70 degrees C until assayed for cytokines. PF was aspirated from the pouch of Douglas. Peripheral and PF samples were analyzed by ELISA in terms of IL-2, IL-4, IL-10 and IFN-gamma. Determinations of T helper, T suppressor, NK, and B cells were assessed by using cluster determinant-3 (CD-3), CD4, CD8, CD25, CD28, CD45, CD16, CD23 and antibodies against early T cell activation antigens such as CD45RA/CD45RO, CD-69 and late activation antigens such as HLA-DR. A multiparameter flow cytometry was applied to detect the cell activation antigen expression. RESULTS: In terms of cytokine levels in PB and PF’s of control group and early- and late-staged endometriosis cases, no significant difference was depicted in the cytokine levels (p > 0.05). Levels of immune cells did not differ between three groups (p > 0.05). CONCLUSIONS: The result of this study did not show any significant difference in PB and PF cytokine and lymphocyte subgroups between normal and early- and late-staged endometriosis.

Fertil Steril. 2009 Oct;92(4):1221-7. Epub 2008 Nov 19.

Two novel serum biomarkers for endometriosis screened by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry and their change after laparoscopic removal of endometriosis.

Jing J, Qiao Y, Suginami H, Taniguchi F, Shi H, Wang X.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, People’s Republic of China. jijiho66@163.com

OBJECTIVE: To explore novel endometriosis serum biomarkers by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). DESIGN: First, we aimed to discover the potential biomarkers of endometriosis by SELDI-TOF-MS. Second, blinded test was performed to characterize the effectiveness of the model by examining the sensitivity and specificity. Third, 29 postoperative patients with endometriosis were recruited to monitor the change of potential biomarkers after laparoscopic surgery. SETTING: Collaborative investigation in an academic research environment. PATIENT(S): Fifty-nine patients with endometriosis, 31 patients without endometriosis, and 30 healthy volunteers. INTERVENTION(S): Blood serum of endometriosis and control group patients. MAIN OUTCOME MEASURE(S): Protein expression. RESULT(S): Two endometriosis-specific proteins were found in the preliminary screening study. Furthermore, the blinded test was performed and showed a sensitivity of 86.67% and a specificity of 96.77% of the markers for detecting endometriosis, which are significantly higher than those of CA-125 for distinguishing patients with endometriosis from patients without endometriosis. After surgery, the levels of these biomarker proteins decreased to levels comparable with those of patients without endometriosis. CONCLUSION(S): We discovered the potential biomarkers of endometriosis and set up a diagnostic model with a sensitivity of 86.67% and a specificity of 96.77%, which is significantly higher than that of CA-125 for detecting endometriosis, The levels of these proteins decreased to levels comparable with those of patients without endometriosis.

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Biol Reprod. 2009 Apr;80(4):649-56. Epub 2008 Nov 19.

Reduced fecundity in female rats with surgically induced endometriosis and in their daughters: a potential role for tissue inhibitors of metalloproteinase 1.

Stilley JA, Woods-Marshall R, Sutovsky M, Sutovsky P, Sharpe-Timms KL.

Department of Obstetrics, Gynecology and Women’s Health, University of Missouri, Columbia, Missouri 65212, USA.

The cause of reduced fecundity in women with endometriosis is unknown. Expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by both ectopic and eutopic endometrium reportedly has a role in the pathogenesis of endometriosis. We hypothesize that anomalous endometriotic TIMP protein synthesis, secretion, and localization also cause reproductive pathologies resulting in reduced fecundity. An established rat model for endometriosis (Endo) compared with nonendometriotic controls (Shams) was used to investigate reduced fecundity in endometriosis. Comparing Endo and Sham rats, Endo rats had altered ovarian dynamics, including fewer ovarian follicles and corpora lutea with luteinized unruptured follicles. Furthermore, in vivo anomalies in postovulatory oocyte structure and preimplantation embryo development, including misaligned chromosomes, nuclear and cytoplasmic fragmentation, and delayed or arrested cleavage, as well as spontaneous abortions, were found only in Endo rats. A causative role for TIMP1 in these phenomena is supported by our findings that Endo rats have more TIMP1 in their peritoneal fluid as detected by ELISA and more TIMP1 immunolocalization in the theca of antral follicles as measured by computer-assisted morphometric analysis. These data suggest that in endometriosis the accumulation of TIMP1 disrupts the normal MMP/TIMP enzymatic milieu in the peritoneal cavity and negatively affects ovarian dynamics, oocyte quality, and preimplantation embryo development, thereby decreasing fecundity. Most intriguingly, daughters of Endo rats that had no experimental interventions exhibited these same reproductive abnormalities. We predict that developmental exposure to endometriosis leads to permanent epigenetic changes in subsequent generations.

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Cancer Sci. 2009 Jan;100(1):9-16. Epub 2008 Oct 23.

Role of iron in carcinogenesis: cancer as a ferrotoxic disease.

Toyokuni S.

Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan. toyokuni@med.nagoya-u.ac.jp

Iron is abundant universally. During the evolutionary processes, humans have selected iron as a carrier of oxygen inside the body. However, iron works as a double-edged sword, and its excess is a risk for cancer, presumably via generation of reactive oxygen species. Thus far, pathological conditions such as hemochromatosis, chronic viral hepatitis B and C, exposure to asbestos fibers, as well as endometriosis have been recognized as iron overload-associated risks for human cancer. Indeed, iron is carcinogenic in animal experiments. These reports unexpectedly revealed that there are target genes in iron-induced carcinogenesis and that iron-catalyzed oxidative DNA damage is not random in vivo. Several iron transporters and hepcidin, a peptide hormone regulating iron metabolism, were discovered in the past decade. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy decreased cancer risk in the apparently normal population. These results warrant reconsideration of the role of iron in carcinogenesis and suggest that fine control of body iron stores would be a wise strategy for cancer prevention.

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Int J Gynaecol Obstet. 2009 Feb;104(2):156-60. Epub 2008 Nov 18.

Transvaginal ultrasound for diagnosis of deeply infiltrating endometriosis.

Goncalves MO, Dias JA Jr, Podgaec S, Averbach M, Abrão MS.

RDO and Digimagem Diagnósticos Médicos, São Paulo, SP, Brazil.

Deeply infiltrating endometriosis is the clinical form of the disease that is generally associated with conditions of more intense pain and may require more complex surgical management, consequently resulting in greater risks to the patient. In recent years, various investigators have confirmed the usefulness of methods such as magnetic resonance imaging (MRI), transrectal ultrasound and transvaginal ultrasound (TVUS) for the diagnosis of deep endometriotic lesions. The objectives of the present study are to describe the method used to perform TVUS for the detection of deeply infiltrating endometriosis, and to discuss the clinical benefits that the data obtained may offer clinicians providing care for patients suspected of having this type of endometriosis.

Mol Cell Endocrinol. 2009 Mar 25;301(1-2):216-24. Epub 2008 Oct 25.

Estrone C15 derivatives–a new class of 17beta-hydroxysteroid dehydrogenase type 1 inhibitors.

Messinger J, Husen B, Koskimies P, Hirvelä L, Kallio L, Saarenketo P, Thole H.

Solvay Pharmaceuticals Research Laboratories, Hans-Böckler-Allee 20, D-30173 Hannover, Germany. josef.messinger@solvay.com

Lowering local estradiol concentration by inhibition of the estradiol-synthesizing enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) has been proposed as a promising new therapeutic option to treat estrogen-dependent diseases like endometriosis and breast cancer. Based on a molecular modelling approach we designed and synthesized novel C15-substituted estrone derivatives. Subsequent biological evaluation revealed that potent inhibitors of human 17beta-HSD1 can be identified in this compound class. The best, compound 21, inhibited recombinant human 17beta-HSD1 with an IC50 of 10nM and had no effect on the activity of recombinant human 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2), the enzyme catalyzing estradiol inactivation. These properties were retained in a cell-based enzyme activity assays. In spite of the estrogen backbone compound 21 did not show estrogen receptor mediated effects in vitro or in vivo. In conclusion, estrone C15 derivative compound 21 can be regarded as a promising lead compound for further development as a 17beta-HSD1 inhibitor.

Biochem Pharmacol. 2009 Jan 15;77(2):204-15. Epub 2008 Nov 1.

Novel progesterone receptor modulators with gene selective and context-dependent partial agonism.

Berrodin TJ, Jelinsky SA, Graciani N, Butera JA, Zhang Z, Nagpal S, Winneker RC, Yudt MR.

Women’s Health & Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19101-2528, USA

Progesterone receptor (PR) modulators are used in contraception and post-menopausal hormone therapy, and are under clinical development for reproductive disorders such as uterine fibroids and endometriosis. Development of tissue selective PR modulators (SPRMs) with reduced side effects and improved pharmacology represents a large unmet medical need in the area of women’s health. One approach to addressing this need is to focus on the two PR isoforms PR-A and PR-B. In vitro and in vivo studies have revealed both distinct as well as overlapping gene regulation and functional responses of the two PR isoforms that suggests that PR-A selective modulators may retain a desired biological profile. We have identified a chemical series of 4-(4-chlorophenyl)-substituted piperazine carbimidothioic acid esters (PCEs) that have partial PR agonist activity and selectively activate some PR-A isoform regulated genes in T47D cells. However, full microarray analysis in these cells does not predict a global isoform selective profile for these compounds, but rather a unique gene-selective profile is observed relative to steroidal progestins. Using multiplexed peptide interaction profiling and co-activator recruitment assays we find that the mechanism of partial agonism is only partly defined by the ability to recruit known co-activators or peptides but also depends on the cell and promoter context of the gene under investigation. The data demonstrate global consequences of mechanistic and functional differences that can lead to selective biological responses of novel steroid receptor modulators.

Reprod Sci. 2009 Jan;16(1):43-55. Epub 2008 Nov 14.

Ultrastructure of ectopic peritoneal lesions from women with endometriosis, including observations on the contribution of coelomic mesothelium.

Jones CJ, Nardo LG, Litta P, Fazleabas AT.

Maternal and Fetal Health Research Centre, School of Clinical and Laboratory Science, University of Manchester, St. Mary’s Hospital, Manchester, United Kingdom. carolyn.jones@ manchester.ac.uk

Following a study in a baboon model of endometriosis, we here describe the morphology of ectopic peritoneal lesions in the human to examine the effects of an ectopic site on glandular structure and function. Ectopic biopsies from 17 women with endometriosis were fixed and processed for electron microscopy. Certain biopsies were also probed for intermediate filaments using immunohistochemistry. Ultrastructurally, lesions showed many different glandular morphologies with indications of delayed maturation compared to normal endometrium. Mesothelium covered some lesions and there was evidence of mesothelial invasion into the stroma. Ectopic endometriotic lesions from women with endometriosis showed ultrastructural differences from eutopic endometrium, with indications that mesothelial invasion may contribute to gland development in some lesions.

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Eur J Obstet Gynecol Reprod Biol. 2009 Jan;142(1):53-6. Epub 2008 Nov 17.

Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis.

Sepulcri Rde P, do Amaral VF.

Graduate Studies in Health Sciences, Pontificia Universidade Católica do Paraná, Curitiba, Brazil.

OBJECTIVE: To assess depressive symptoms, anxiety and quality of life in women with pelvic endometriosis. STUDY DESIGN: A prospective study of 104 women diagnosed with pelvic endometriosis. The Beck Depression Inventory (BDI) and the Hamilton Rating Scale for Depression (HAM-D) were used to evaluate depressive symptoms; the Spielberger State-Trait Anxiety Inventory (STAI) and the Hamilton Rating Scale for Anxiety (HAM-A) to evaluate anxiety symptoms; and the short (26-item) version of the World Health Organization Quality Of Life instrument (WHOQOL-BREF) to evaluate quality of life. RESULTS: Of the patients evaluated, 86.5% presented depressive symptoms (mild in 22.1%, moderate in 31.7%, and severe in 32.7%) and 87.5% presented anxiety (minor in 24% and major in 63.5%). Quality of life was found to be substandard. Age correlated positively with depressive symptoms, as determined using the BDI (P=0.013) and HAM-D (P=0.037). There was a positive correlation between current pain intensity and anxiety symptoms, as assessed using the STAI (state, P=0.009; trait, P=0.048) and HAM-A (P=0.0001). The complaints related to physical limitations increased in parallel with the intensity of pain (P=0.017). There was an inverse correlation between duration of treatment and quality of life (P=0.017). There was no correlation between psychiatric symptoms and endometriosis stage. CONCLUSIONS: A rational approach to endometriosis should include an evaluation of the emotional profile and quality of life. That approach would certainly reduce the functional damage caused by the endometriosis.

Chem Biol Interact. 2009 Mar 16;178(1-3):158-64. Epub 2008 Oct 22.

Derivatives of pyrimidine, phthalimide and anthranilic acid as inhibitors of human hydroxysteroid dehydrogenase AKR1C1.

Brozic P, Cesar J, Kovac A, Davies M, Johnson AP, Fishwick CW, Lanisnik Rizner T, Gobec S.

Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, Ljubljana, Slovenia.

Human hydroxysteroid dehydrogenase (HSD) AKR1C1 is a member of the aldo-keto reductase superfamily, and it functions mainly as a 20alpha-HSD. It catalyzes the reduction of the potent progesterone to the weak 20alpha-hydroxyprogesterone, and of 3alpha,5alpha-tetrahydroprogesterone (5alpha-THP; allopregnanolone) to 5alpha-pregnane-3alpha,20alpha-diol. AKR1C1 thus decreases the levels of progesterone and 5alpha-THP in peripheral tissue. Progesterone inhibits cell proliferation, stimulates differentiation of endometrial cells, and is also important for maintenance of pregnancy, while 5alpha-THP allosterically modulates the activity of the gamma-aminobutyric acid receptor. Inhibitors of AKR1C1 are thus potential agents for treatment of endometrial cancer and endometriosis, as well as other diseases like premenstrual syndrome, catamenial epilepsy and depressive disorders.We have synthesized a series of pyrimidine, phthalimido and athranilic acid derivatives, and have here examined their inhibitory properties towards AKR1C1. A common aldo-keto reductase substrate, 1-acenaphthenol, was used to monitor the NAD(+)-dependent oxidation catalyzed by AKR1C1. The most potent inhibitors of AKR1C1 were the pyrimidine derivative N-benzyl-2-(2-(4-methoxybenzyl)-6-oxo-1,6-dihydropyrimidin-4-yl)acetamide (K(i)=17 microM) and the anthranilic acid derivative 2-(((2′,3-dichlorobiphenyl-4-yl)carbonyl)(methyl)amino)benzoic acid (K(i)=33 microM), both of which are non-competitive inhibitors.

Reprod Sci. 2009 Feb;16(2):140-6. Epub 2008 Nov 11.

Mechanistic and therapeutic implications of angiogenesis in endometriosis.

Taylor RN, Yu J, Torres PB, Schickedanz AC, Park JK, Mueller MD, Sidell N.

Department of Gynecology and Obstetrics, Human Uterine Biology Program, Emory University School of Medicine, Atlanta, Georgia 30322, USA. robert.n.taylor@emory.edu

Like tumor metastases, endometriotic implants require neovascularization to proliferate and invade into ectopic sites within the host. Endometrial tissue, with its robust stem cell populations and remarkable regenerative capabilities, is a rich source of proangiogenic factors. Among the most potent and extensively studied of these proteins, vascular endothelial growth factor has emerged as a critical vasculogenic regulator in endometriosis. Accordingly, angiogenesis of the nascent endometriotic lesion has become an attractive target for novel medical therapeutics and strategies to inhibit vascular endothelial growth factor action. Vascular endothelial growth factor gene regulation in endometrial and endometriosis cells by nuclear receptors, other transcription factors, and also by infiltrating immune cells is emphasized. New data showing that oxidative and endoplasmic reticulum stress increase vascular endothelial growth factor expression are provided. Finally, we review the clinical implications of angiogenesis in this condition and propose potential antiangiogenic therapies that may become useful in the control or eradication of endometriotic lesions.

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Reprod Sci. 2009 Feb;16(2):147-51. Epub 2008 Nov 11.

Endometrial angiogenesis, vascular maturation, and lymphangiogenesis.

Rogers PA, Donoghue JF, Walter LM, Girling JE.

Centre for Women’s Health Research, Monash University, Department of Obstetrics and Gynaecology and Monash Institute for Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia. peter.rogers@med.monash.edu.au

Angiogenesis, arteriogenesis or vessel maturation, and lymphangiogenesis comprise a continuum of vascular development, with overlap and interaction between the mechanisms by which they are controlled. These processes are of clinical interest because they play roles in endometrial repair, placental development, and in gynecological disorders including endometrial cancer, endometriosis and abnormal uterine bleeding. Using mouse models we have shown that estrogen can be either proangiogenic or antiangiogenic in endometrium. Progesterone alone is proangiogenic, although this can be moderated by pretreatment with estrogen. Arteriogenesis also increases in response to progesterone, and this effect is not inhibited by estrogen. Lymphatics account for 13% of all vessels in the human functionalis compared to 57% in the basalis. Many of the basalis lymphatic vessels are closely associated with spiral arterioles and this intimate connection may provide a mechanism for paracrine communication between the functionalis and the arteries supplying the endometrium.

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J Clin Endocrinol Metab. 2009 Feb;94(2):623-31. Epub 2008 Nov 11.

Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis.

Attar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, Gurates B, Attar R, Yaegashi N, Hales DB, Bulun SE.

Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, 303 East Superior Street, 4-123, Chicago, Illinois 60611, USA.

CONTEXT: Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E2 (PGE2) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream-transcription factor (COUP-TF) and Wilms’ tumor-1 (WT1) in endometrium. OBJECTIVE: The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE2-stimulated estrogen production in endometriotic cells and endometrium. RESULTS: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3beta-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells. CONCLUSION: Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters of StAR and aromatase genes in a synchronous fashion.

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J Clin Endocrinol Metab. 2009 Feb;94(2):615-22. Epub 2008 Nov 11.

Estrogen receptor (ER) beta regulates ERalpha expression in stromal cells derived from ovarian endometriosis.

Trukhacheva E, Lin Z, Reierstad S, Cheng YH, Milad M, Bulun SE.

Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, 303 East Superior Street, 4-123, Chicago, Illinois 60611, USA.

CONTEXT: Estradiol and its nuclear receptors, estrogen receptor (ER) alpha and ERbeta, play critical roles in endometrium and endometriosis. Levels of ERbeta, due to pathological hypomethylation of its promoter, are significantly higher in endometriotic vs. endometrial tissue and stromal cells, whereas ERalpha levels are lower in endometriosis. Estradiol regulates ERalpha gene expression via its alternatively used promoters A, B, and C. OBJECTIVE: The aim of the study was to determine whether high levels of ERbeta in endometriotic stromal cells from ovarian endometriomas regulate ERalpha gene expression. RESULTS: ERbeta knockdown significantly increased ERalpha mRNA and protein levels in endometriotic stromal cells. Conversely, ERbeta overexpression in endometrial stromal cells decreased ERalpha mRNA and protein levels. ERbeta knockdown significantly decreased proliferation of endometriotic stromal cells. Chromatin immunoprecipitation assays demonstrated that estradiol enhanced ERbeta binding to nonclassical activator protein 1 and specificity protein 1 motifs in the ERalpha gene promoters A and C and a classic estrogen response element in promoter B in endometriotic stromal cells. CONCLUSIONS: High levels of ERbeta suppress ERalpha expression and response to estradiol in endometrial and endometriotic stromal cells via binding to classic and nonclassic DNA motifs in alternatively used ERalpha promoters. ERbeta also regulates cell cycle progression and might contribute to proliferation of endometriotic stromal cells. We speculate that a significantly increased ratio of ERbeta:ERalpha in endometriotic tissues may also suppress progesterone receptor expression and contribute to progesterone resistance. Thus, ERbeta may serve as a significant therapeutic target for endometriosis.

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Gynecol Obstet Invest. 2009;67(2):118-26. Epub 2008 Nov 6.

Expression of the epidermal growth factor system in eutopic endometrium from women with endometriosis differs from that in endometrium from healthy women.

Ejskjaer K, Sorensen BS, Poulsen SS, Mogensen O, Forman A, Nexo E.

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

BACKGROUND: The epidermal growth factor (EGF) system comprises four receptors, HER1-4, and several ligands, and is cyclically expressed in endometrium from healthy fertile women. Our aim is to identify differences in expression of the EGF system between endometriotic and normal endometrium. METHODS: We previously examined the EGF system in endometrial samples from healthy women (n = 14). Here we examine samples from endometrium (n = 23), endometriomas (n = 10) and peritoneal endometriosis (n = 9) from women with endometriosis (n = 23). mRNA expression of receptors and ligands from the EGF system was analyzed by real-time PCR, and proteins were localized by immunohistochemistry. RESULTS: Endometrial mRNA for HER1-3 was high compared with our previous findings in healthy endometrium, whereas HER4 and the ligands were unchanged. Endometriomas show lower expression of HER1-3 and no HER4 expression. Significant differences were demonstrated in late secretory phase for HER1 and HER2 and in the proliferative phase for HER3 compared to healthy women. Immunohistochemically, HER2 was identified in all samples, predominately in glands and surface epithelium. In a few glands, HER2 was in both cytoplasm and cell membrane. CONCLUSION: We report quantitative and qualitative differences in the EGF system in endometriotic eutopic endometrium compared to endometrium from healthy individuals.

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Mol Cell Endocrinol. 2009 Mar 25;301(1-2):154-7. Epub 2008 Oct 15.

Development of a biological screening system for the evaluation of highly active and selective 17beta-HSD1-inhibitors as potential therapeutic agents.

Kruchten P, Werth R, Marchais-Oberwinkler S, Frotscher M, Hartmann RW.

8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbrücken, Germany.

17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses the intracellular conversion of oestrone (E1) to oestradiol (E2). E2 is known to be involved in the development and progression of breast cancer and endometriosis. Since 17beta-HSD1 is overexpressed in these oestrogen-dependent diseases, inhibition of this enzyme may be a more target-directed therapeutical approach compared to established medical treatments. For the identification of highly active and selective 17beta-HSD1-inhibitors that are suitable for application as potential therapeutics, there is a need for an appropriate, efficient and reliable screening system. Here, we report the development and application of our screening system using our in house library of potential 17beta-HSD1-inhibitors. Four potent and selective compounds with a good first pharmacokinetic profile were identified.

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Hum Reprod. 2009 Feb;24(2):408-14. Epub 2008 Nov 1.

Tunicamycin enhances the apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand in endometriotic stromal cells.

Hasegawa A, Osuga Y, Hirota Y, Hamasaki K, Kodama A, Harada M, Tajima T, Takemura Y, Hirata T, Yoshino O, Koga K, 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.

BACKGROUND: The increase in concentration of osteoprotegerin, an antagonist of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in the peritoneal fluid of women with endometriosis may interfere with TRAIL-induced apoptosis in endometriotic cells and promote the development of endometriosis. In the present study, the effect of tunicamycin, a possible apoptosis enhancer, on TRAIL-induced apoptosis in endometriotic stromal cells (ESC) was determined. METHODS: ESC were isolated from cyst walls of ovarian endometrioma and cultured. ESC were incubated with or without tunicamycin (2 microg/ml) for the first 16 h, and then incubated with or without TRAIL (200 ng/ml) for the following 24 h. To examine whether caspases were involved in TRAIL-induced apoptosis, z-VAD-fmk (30 microM), a general caspase inhibitor, was added 1 h before TRAIL treatment. ESC were transfected with small interfering RNA (siRNA) for DR5, a receptor of TRAIL, before tunicamycin treatment to evaluate its role in ESC. DR5 mRNA level was determined by quantitative RT-PCR. Apoptosis in ESC was evaluated by flow cytometry. RESULTS: Tunicamycin increases both DR5 mRNA (P < 0.005) and TRAIL-induced apoptosis (P < 0.0001) in ESC. The increase in TRAIL-induced apoptosis in ESC by tunicamycin was suppressed (P < 0.05) by z-VAD-fmk. Transfection with DR5 siRNA suppressed the tunicamycin-induced increase in DR5 mRNA and abrogated the up-regulation of TRAIL-induced apoptosis by tunicamycin. CONCLUSIONS: The combined treatment with tunicamycin and TRAIL may have therapeutic potential in the treatment of endometriosis.

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Presse Med. 2009 Jan;38(1):e1-6. Epub 2008 Nov 1.

Parietal endometriosis in abdominal wall

[Article in French]

Boufettal H, Hermas S, Boufettal R, Jai SR, Kamri Z, Elmouatacim K, Noun M, Samouh N.

Service de gynécologie, Obstétrique C, Maternité Lalla Meryem, Centre hospitalier universitaire Ibn Rochd, Casablanca, Maroc. mohcineb@yahoo.fr

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Fertil Steril. 2009 Mar;91(3):930.e19-22. Epub 2008 Nov 1.

Pneumoperitoneum associated with catamenial pneumothorax in women with thoracic endometriosis.

Jablonski C, Alifano M, Regnard JF, Gompel A.

Université Paris Descartes, Paris, France. christine.jablonski@htd.aphp.fr

OBJECTIVE: To elucidate the pathophysiology of catamenial pneumothorax (CP) due to thoracic endometriosis and support the theory of the transdiaphragmatic passage of air from the genital tract through diaphragmatic perforations caused by endometrial implants. DESIGN: Three case reports. SETTING: Academic hospital. PATIENT(S): Three women with pneumoperitoneum concomitant to CP. INTERVENTION(S): Thoracic/abdominal computed tomography scans and chest x-rays. MAIN OUTCOME MEASURE(S): Presence of pneumoperitoneum coexisting with CP. RESULT(S): The observation of pneumoperitoneum associated with CP supports the theory of the transdiaphragmatic passage of air, which implies the occurrence of a pneumoperitoneum as an intermediate step. CONCLUSION(S): Our three cases strongly support the theory of the transdiaphragmatic passage of air in the pathogenesis of CP.

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J Minim Invasive Gynecol. 2009 Jan-Feb;16(1):34-9. Epub 2008 Oct 30.

Postoperative long-term maintenance therapy with oral contraceptives after gonadotropin-releasing hormone analog treatment in women with ovarian endometrioma.

Park HJ, Koo YA, Yoon BK, Choi D.

Department of Obstetrics and Gynecology, Samsung Medical Center, Seoul, Korea.

STUDY OBJECTIVE: The goal of this preliminary study was to assess the effect of cyclic monophasic oral contraceptives (OCs) as a postoperative long-term maintenance therapy (median 33.2 months) to suppress recurrence of endometrioma after conservative ovarian surgery followed by gonadotropin-releasing hormone (GnRH) analog treatment. DESIGN: Retrospective clinical study (Canadian Task Force classification II-2). SETTING: Adolescent and premarital clinic in a university hospital. PATIENTS: The study was performed on 51 patients who underwent conservative surgery for endometrioma followed by GnRH analog treatment for 6 months. INTERVENTIONS: We used cyclic monophasic OCs as maintenance therapy after surgical and medical treatment with GnRH analog for 6 months. MEASUREMENTS AND MAIN RESULTS: Cyclic monophasic OCs were offered to young patients (n=51, age=24.1+/-2.8 years) who did not want to conceive immediately, to prevent the recurrence of endometrioma after conservative surgery with 6 cycles of postoperative GnRH analog treatment. During the long-term follow-up period (median 41.2; range 19-94 months), no recurrences of the endometrioma occurred in the current OC users. One patient showed a recurrence of endometrioma at 12 months after the discontinuation of the OCs. The median duration of OC administration was 33.20 months (range 12-86). In addition, 4 of 10 patients became pregnant within 12 months of discontinuing the long-term OC therapy. CONCLUSION: Postoperative long-term maintenance therapy with OCs can effectively suppress endometrioma recurrence in adolescent and young patients.

Fertil Steril. 2009 Oct;92(4):1234-9. Epub 2008 Oct 31.

Effect of progestogens and combined oral contraceptives on nerve fibers in peritoneal endometriosis.

Tokushige N, Markham R, Russell P, Fraser IS.

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

OBJECTIVE: To investigate how progestogens and combined oral contraceptives change nerve fiber density in peritoneal endometriotic lesions and to identify the types of nerve fibers still present during hormone treatment. DESIGN: Laboratory study using human tissue. SETTING: University-based laboratory. PATIENT(S): Hormonally treated and untreated women with endometriosis undergoing laparoscopy, hysteroscopy, and curettage. INTERVENTION(S): Biopsy samples from peritoneal endometriotic lesions in hormonally treated and untreated women with endometriosis. MAIN OUTCOME MEASURE(S): Types and density of nerve fibers were immunohistochemically determined in peritoneal endometriotic lesions from hormonally treated and untreated women with endometriosis. RESULT(S): The nerve fiber density (mean +/- standard deviation/mm(2)) in peritoneal endometriotic lesions from hormone-treated women with endometriosis (10.6 +/- 2.2/mm(2)) was statistically significantly lower than in peritoneal endometriotic lesions from untreated women with endometriosis (16.3 +/-10.0/mm(2)). Nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions were slightly reduced in hormone-treated women with endometriosis compared with untreated women with endometriosis. CONCLUSION(S): Progestogens and combined oral contraceptives reduced nerve fiber density and nerve growth factor and nerve growth factor receptor p75 expression in peritoneal endometriotic lesions.

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Fertil Steril. 2009 Feb;91(2):316-9. Epub 2008 Oct 30.

Fertility preservation: state of the science and future research directions.

Lamar CA, DeCherney AH.

OBJECTIVE: To identify issues related to fertility preservation, discuss the state of the science, and make specific recommendations to guide future research supported by the U.S. National Institutes of Health in the field of fertility preservation. DESIGN: A 1-day meeting of an expert advisory panel convened by the Eunice Kennedy Shriver National Institute of Child Health and Human Development on January 23, 2007, at the National Institutes of Health in Bethesda, Maryland. The panelists represented the disciplines of reproductive endocrinology and infertility, urology, neurobiology, physiology, radiation oncology, pediatrics, genetics, behavioral science, surgery, and occupational health. CONCLUSION(S): The panel members recognized the emerging focus on fertility preservation to help women and men have biological children. Among those who might benefit from research in this area are those at risk for impaired fertility or infertility, including not only cancer survivors but also others with genetic predispositions to infertility, environmental occupational exposure to hazardous substances or conditions, or reproductive diseases such as endometriosis. The panelists highlighted the need for education and awareness among health-care providers to help people understand options for preserving fertility, the need for technologic advances, the lack of data on long-term consequences of fertility preservation, and emerging ethical and social questions. This report describes the process for developing a multidisciplinary, collaborative approach for research in this area, summarizes the discussions of the panelists, and outlines the recommendations for future research.

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Fertil Steril. 2009 Apr;91(4 Suppl):1574-7. Epub 2008 Oct 29.

Aromatase inhibitors prevent the estrogen rise associated with the flare effect of gonadotropins in patients treated with GnRH agonists.

Bedaiwy MA, Mousa NA, Casper RF.

Reproductive Research Center, Cleveland Clinic, Cleveland, Ohio, USA.

This was a preliminary study to determine the effect of aromatase inhibitors in preventing the flare induced by GnRH agonist (GnRH-a) in women with endometriosis (n = 9) or leiomyomata (n = 4) who were given letrozole on the first 5 days of the GnRH-a therapy. Serum LH and FSH levels showed the typical flare 1 day after the injection of the GnRH-a; however, E(2) declined immediately after letrozole administration and was notably suppressed at 1, 2, and 4 days after GnRH-a. No patients complained of clinical symptoms typical of the GnRH-a flare phenomenon.

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Urology. 2009 Jan;73(1):47-51. Epub 2008 Oct 31.

Urinary tract endometriosis: clinical, diagnostic, and therapeutic aspects.

Pérez-Utrilla Pérez M, Aguilera Bazán A, Alonso Dorrego JM, Hernández A, de Francisco MG, Martín Hernández M, de Santiago J, de la Peña Barthel J.

Department of Urology, La Paz University Hospital, Madrid, Spain.

OBJECTIVES: To describe our experience at La Paz University Hospital with 12 patients with urinary tract endometriosis, an uncommon pathologic finding, the most extensive series published by Spanish investigators to our knowledge. METHODS: We performed a retrospective analysis of 12 cases of urinary tract endometriosis diagnosed from 1993 to 2008. RESULTS: The mean patient age was 37.75 years. Of the 12 patients, 5 had bladder involvement and 7 had ureteral involvement, 2 bilateral, 2 left, and 3 right. In those with bladder endometriosis, the diagnosis was made by cystoscopy and biopsy in 4 patients. Treatment consisted of laparoscopic hysterectomy and partial cystectomy in 1 patient and exploratory laparotomy, transvesical resection, and transurethral resection of the bladder in 3 patients. One of the patients who underwent transurethral resection of the bladder experienced 2 relapses. The first relapse was treated with transurethral resection of the bladder and the second with laparoscopic partial cystectomy. In the patients with ureteral endometriosis, the diagnosis was mainly established by magnetic resonance imaging. Treatment consisted of ureteroneocystostomy in 5 patients (bilateral in 1) and laparoscopic ureterolysis in 2, with later ureteral resection and end-to-end anastomosis in 1 of them. The patient who underwent bilateral ureteroneocystostomy finally required right autotransplantation because of early ureteral relapses. CONCLUSIONS: Urinary tract endometriosis is an uncommon pathologic finding. Surgery is the treatment of choice. We believe partial cystectomy should be considered as an initial option in selected cases, depending on the extent and location of lesions. For cases of ureteral endometriosis, the initial technique depends on the location and depth of the lesion.

Mol Cell Endocrinol. 2009 Mar 25;301(1-2):205-11. Epub 2008 Oct 4.

Structure-activity study in the class of 6-(3′-hydroxyphenyl)naphthalenes leading to an optimization of a pharmacophore model for 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) inhibitors.

Marchais-Oberwinkler S, Frotscher M, Ziegler E, Werth R, Kruchten P, Messinger J, Thole H, Hartmann RW.

8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany.

17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the transformation of estrone (E1) into the most potent estrogen, estradiol (E2), which stimulates cell proliferation and decreases apoptosis. 17beta-HSD1 is often strongly overexpressed in estrogen-dependent diseases (like breast cancer and endometriosis). Thus, this over expressed enzyme is a promising novel target for the development of selective inhibitors, which could be used as drugs for the treatment of these diseases. Using a structure- and ligand-based approach, a pharmacophore model was proposed and a new class of non-steroidal inhibitors of 17beta-HSD1 was designed. Enzyme inhibition was evaluated in vitro using the human enzyme. After identification of the 6-(3′-hydroxyphenyl)-2-naphthol scaffold 1, the potency of this class of inhibitors was further improved by substitution of the 1-position of the naphthalene ring by a phenyl group (compound 18, IC(50)=20nM). Compound 18 also showed a good selectivity toward 17beta-HSD2 and the estrogen receptors alpha and beta.

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Hum Reprod. 2009 Feb;24(2):254-69. Epub 2008 Oct 23.

Surgery for endometriosis-associated infertility: a pragmatic approach.

Vercellini P, Somigliana E, Viganò P, Abbiati A, Barbara G, Crosignani PG.

Gynaecologic Surgery Division, Department of Obstetrics and Gynaecology, University of Milan, via Commenda 12, 20122 Milano, Italy. paolo.vercellini@unimi.it

Laparoscopic treatment for endometriosis-associated infertility is gaining widespread popularity supported mostly by uncontrolled studies, but the purported benefit of surgery may be overvalued. We have therefore analysed the best available evidence with the aim of defining an approximate estimate of the effect size of conservative surgery for infertile women with endometriosis in various clinical conditions. The overall increase in post-operative likelihood of conception over background pregnancy rate may be estimated to be between 10 and 25%. The effect of surgery for peritoneal lesions is limited, and an estimate of benefit should be decreased by the fact that preoperative identification of the subjects actually with the condition is unfeasible. The benefit of excision of ovarian endometriomas is difficult to define due to multiple confounding factors and methodological drawbacks in the considered studies. Excision of rectovaginal endometriosis is of doubtful value and associated with worrying morbidity. The role of surgery before, after or as an alternative to IVF needs clarification. In conclusion, the absolute benefit increase of surgery for endometriosis-associated infertility appears smaller than previously believed. Complete and detailed information on risks and benefits of treatment alternatives must be offered to infertile patients to allow unbiased choices between possible options.

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