Hum Reprod. 2009 Feb;24(2):398-407. Epub 2008 Oct 23.

Peritoneal macrophage depletion by liposomal bisphosphonate attenuates endometriosis in the rat model.

Haber E, Danenberg HD, Koroukhov N, Ron-El R, Golomb G, Schachter M.

Faculty of Medicine, Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel.

BACKGROUND: Activation of macrophages is central to the implantation of endometriosis (EM). We examined the hypothesis that macrophage depletion by intraperitoneal (IP) injection of liposomal alendronate (LA) could result in EM attenuation in a rat model, thus supporting the notion of the pivotal role of macrophages in EM pathology. METHODS: In this study, 90 rats were subjected to an EM model and were divided randomly into seven groups: five groups were treated by 4x once-weekly IP injections of LA (0.02, 0.1, 1, 5 or 10 mg/kg) and the other two groups received saline injections (control) or empty liposomes. Sham-operated rats also received empty liposomes. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Four weeks after the initial surgery, the number, size and weight of implants were recorded, adhesions were graded, macrophage infiltration was assessed and the peritoneal fluid was analyzed for monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor alpha (TNFalpha). RESULTS: Monocyte depletion following IP LA administration resulted in an inhibitory effect on the initiation and growth of EM implants, as expressed by implantation rate, adhesion scoring, implants’ size and weight (>0.1 mg/kg LA, P < 0.05). Reduced numbers of infiltrating macrophages were observed in implants of the 1 mg/kg LA group. Peritoneal fluid MCP-1 levels were negatively correlated with LA dose (P < 0.001), whereas no significant correlation could be found for TNFalpha. CONCLUSIONS: Macrophage depletion using IP LA has been shown to effectively inhibit the initiation and growth of EM implants, in a rat EM model. The clear dose-response effect may be viewed as a confirmation of the validity of the concept and encourages further study.

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Am J Surg Pathol. 2009 Feb;33(2):278-88.

Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenofibroma.

Gallardo A, Prat J.

Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.

Mullerian adenosarcomas are rare mixed tumors of low malignant potential that occur mainly in the uterus and also in extrauterine locations. Microscopically, they may be difficult to distinguish from adenofibromas. In this clinicopathologic study of 55 adenosarcomas, the mean patient age was 50 years (range: 13 to 83 y). Thirty-seven tumors were of the uterine corpus, 11 of the cervix, 4 of the ovary, and 1 each of the fallopian tube, vagina, and Douglas peritoneum. Abdominal pain and vaginal bleeding were the usual complaints. Treatment was known in 50 patients: 10 had polypectomy, 1 cone biopsy, and 39 hysterectomy, which was accompanied by bilateral salpingo-oophorectomy in 24 and lymphadenectomy in 4. Five patients had radiotherapy and 2 of them had chemotherapy. Stage was known in 41 cases. Of 30 tumors of the uterine corpus, 17 were stage IA, 11 stage IB, 1 stage IC, and 1 stage IIIC. Four cervical tumors were stage IB. Three of the 4 ovarian tumors were stage IA and the other was stage IIIC. The tumor of the fallopian tube was stage IC, and the tumors of the vagina and recto-uterine pouch were confined to their site of origin. Most uterine tumors were polypoid masses ranging from 1 to 20 cm (mean: 6.5 cm). Microscopically, sarcomatous overgrowth was found in 18 cases (33%), heterologous elements in 13 (24%), and sex cordlike differentiation in 7 (13%). Fourteen of 30 uterine tumors (47%) had myometrial invasion that was minimal in 5, involved one-third of the myometrial thickness in 7, and more than 50% in 2. Of 4 cervical tumors, 2 were endocervical polyps, 1 invaded one-third of the cervical wall, and the other invaded its full thickness. Follow-up information (2 mo to 18 y; average: 7.5 y) was available in 29 patients. Six developed metastases and 5 of them died of tumor. Four had adenosarcomas with sarcomatous overgrowth; however, the other 2 patients had typical low-grade adenosarcomas of the uterine corpus and cervix, respectively, exhibiting only mild nuclear atypia of the stromal component and </=2 mitotic figures/10 high power fields. Both were initially underdiagnosed as adenofibromas. The finding of such cases, which raises the controversy of whether or not adenofibroma exists as a tumor entity, prompted us to make a comparative immunohistochemical analysis of 23 typical adenosarcomas, 8 adenosarcomas with sarcomatous overgrowth, and 29 benign and malignant related lesions, including 7 clinically benign adenofibromas. Adenosarcomas with sarcomatous overgrowth showed strong immunoreaction for Ki-67 and p53 and loss of CD10 and progesterone receptors immunostaining; in contrast, the immunoreaction for these tumor markers in typical adenosarcomas without sarcomatous overgrowth was similar to that of adenofibromas associated with favorable outcome and other benign lesions such as endometrial polyps and endometriosis. These findings suggest that some of the tumors currently classified as adenofibromas, on the basis of their low mitotic count and lack of significant nuclear atypia, are, in fact, well-differentiated adenosarcomas.

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Gynecol Obstet Invest. 2009;67(2):81-91. Epub 2008 Oct 16.

Advances in treatment options of endometriosis.

Ozkan S, Arici A.

Department of Obstetrics and Gynecology, Kocaeli University School of Medicine, Kocaeli, Turkey.

Endometriosis, defined as the presence of endometrial tissue outside the uterus, is a challenging condition associated with substantial morbidity. Management of endometriosis must be individualized according to the desired treatment outcome, whether it is relief of pain, improvement of fertility, or the prevention of recurrence. For alleviation of endometriosis-associated pain, medical treatment is generally successful, with no medical agent being more efficacious than another in spite of significantly differing side-effect profiles. Surgical therapy has also been demonstrated to reduce pain scores in comparison with expectant management, although conservative surgery has been frequently associated with recurrence. The efficacy of combination therapies still remains to be clarified. For treatment of endometriosis-associated infertility, suppressive medical treatment has been proven to be detrimental to fertility and should be discouraged, while surgery is probably efficacious for all stages. Controlled ovarian hyperstimulation with intrauterine insemination is recommended in early-stage and surgically corrected endometriosis. Combined surgery with GnRH analog treatment has been proposed to be first-line therapy, followed by IVF as second-line therapy in advanced cases. More rigorously designed randomized clinical trials focusing on the endocrinological, immunological, and genetic aspects of endometriosis are necessary to refine conclusions regarding the etiopathogenesis and therapeutic innovations of this perplexing disease.

Publication Types:

Fertil Steril. 2009 Oct;92(4):1424-7. Epub 2008 Oct 18.

Laparoscopic management of ureteral lesions in gynecology.

De Cicco C, Schonman R, Craessaerts M, Van Cleynenbreugel B, Ussia A, Koninckx PR.

Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.

OBJECTIVE: To investigate the outcome of laparoscopic repair of ureteral injury in laparoscopic gynecologic surgery. DESIGN: Prospective trial. SETTING: University hospital. PATIENT(S): Forty patients with a ureteral lesion in laparoscopic surgery between 1991 and 2007. INTERVENTION(S): Laparoscopic ureteral repair, laparoscopic-assisted or blind stent insertion. MAIN OUTCOME MEASURE(S): Treatment outcome of ureteral lesion analyzed by type of injury, time of diagnosis, and management. RESULT(S): In 4,350 consecutive laparoscopic gynecologic interventions, 42 lesions occurred, 5 during hysterectomy, 1 during adnexectomy, and 36 during deep endometriosis surgery. In the latter group (n = 1,427), the incidence was 1.5% and 21% in women without and with hydronephrosis, respectively. In eight women in whom a stent was inserted after surgery without laparoscopic guidance, five were uneventful and three needed a second intervention. In all 34 women in whom a laparoscopic repair over a stent was performed, the outcome was uneventful, whether diagnosed and treated during surgery (n = 25) or after surgery (n = 9). CONCLUSION(S): Laparoscopic repair over a stent was uneventful for all lacerations, transections, and fistulas, whether performed during or after surgery, and was superior to blind stent insertion. In women with hydronephrosis and deep endometriosis, a preoperative stent insertion seems to be mandatory.

Fertil Steril. 2009 Oct;92(4):1214-20. Epub 2008 Oct 18.

Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression.

Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A.

Research Center, Hospital Universitario La Fe, Valencia, Spain.

OBJECTIVE: To analyze three functional vascular endothelial growth factor (VEGF) polymorphisms (-460C/T, +405G/C, and 936C/T) in women with and without endometriosis and their correlation with VEGF expression in endometrial tissue and peritoneal fluid (PF). DESIGN: Case-control study. SETTING: University-based hospital. PATIENT(S): One hundred eighty-six women with endometriosis and 180 controls without the disease. INTERVENTION(S): Endometrial biopsies were performed by aspiration and PF samples were obtained at laparoscopy. MAIN OUTCOME MEASURE(S): VEGF polymorphisms (-460C/T, +405G/C, and 936C/T) were determined using a polymerase chain reaction (PCR)-restriction fragment length polymorphism assay. Quantitative real-time reverse transcriptase (RT)-PCR assay was used to quantify VEGF-A messenger RNA (mRNA) and VEGF-A antigen levels were quantified by ELISA. RESULT(S): Patients with endometriosis showed a higher VEGF 936T allele frequency than controls. However, the distribution of genotypes and allele frequencies in the other two VEGF (-460C/T, +405G/C) polymorphisms was similar in the endometriosis and control groups. Endometrium and PF from women with endometriosis showed an increase in VEGF levels, but no association was found between the VEGF polymorphisms studied and VEGF expression in endometrial tissue and PF. CONCLUSION(S): These findings suggest that the VEGF 936C/T polymorphism may be associated with the risk of endometriosis in a Caucasian population, but the increased VEGF levels observed in endometriosis do not appear to be associated with this polymorphism.

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Fertil Steril. 2009 Oct;92(4):1228-33. Epub 2008 Oct 17.

A functional promoter polymorphism in interleukin-10 gene influences susceptibility to endometriosis.

Juo SH, Wu R, Lin CS, Wu MT, Lee JN, Tsai EM.

Graduate Institute of Medical Genetics, Kaohsiung Medical University, Kaohsiung, Taiwan.

OBJECTIVE: To investigate the involvement of inflammation in the development of endometriosis. DESIGN: Case-control study to investigate the association between endometriosis and four inflammation-related genes: interleukin (IL)-6, IL-10, IL-1 beta, and cyclooxygenase-2. SETTING: University hospital. PATIENT(S): We had 196 cases with pathologically proved endometriosis and 397 disease-free women as control subjects. INTERVENTION(S): A total of 12 single nucleotide polymorphisms (SNPs) were selected for genotyping, including functional SNPs and common tagging SNPs. MAIN OUTCOME MEASURE(S): Logistic regression and haplotype analyses were performed to evaluate the genetic effect with adjustment for other covariates. RESULT(S): Genotypes at each SNP were in Hardy-Weinberg equilibrium in either case or control subjects, except for rs1800871 at IL-10 in the case subjects (P=.04). We found that the individuals carrying minor allele C of a functional promoter SNP rs1800871 at IL-10 was associated with a reduced risk by approximately twofold compared with the common TT genotype. The T allele was reported to have a lower gene expression level than the C allele, suggesting inadequate suppression of inflammation leading to endometriosis development. Haplotype analysis of the IL-10 gene did not yield a better result. Other genes were not associated with endometriosis. CONCLUSION(S): This study suggests that the functional promoter polymorphism at IL-10 may play a role in the development of endometriosis.

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Fertil Steril. 2009 May;91(5):1926-7. Epub 2008 Oct 18.

Menstrual bleeding from an endometriotic lesion.

Burney RO, Lathi RB.

Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology and Infertility, Stanford University School of Medicine, Stanford, California 94305, USA.

We present a case in which endometriotic lesions were observed to be focally hemorrhagic at laparoscopy performed during menstruation. Red vesicular lesions likely represent early disease with intact capacity for hormonally induced menstrual bleeding.


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Biol Reprod. 2009 Feb;80(2):375-83. Epub 2008 Oct 15.

Erratum in:

  • Biol Reprod. 2009 Jun;80(6):1306.

Characterization of antiestrogenic activity of the Chinese herb, prunella vulgaris, using in vitro and in vivo (Mouse Xenograft) models.

Collins NH, Lessey EC, DuSell CD, McDonnell DP, Fowler L, Palomino WA, Illera MJ, Yu X, Mo B, Houwing AM, Lessey BA.

Department of Obstetrics and Gynecology, Greenville Hospital System, Greenville, South Carolina 29605, USA.

Prunella vulgaris (PV), a commonly used Chinese herb, also known as Self-heal, has a wide range of reported medicinal activities. By screening multiple herbs using the endometrial cancer cell line, ECC-1, and an alkaline phosphatase detection assay, we found that PV displayed significant antiestrogenic activity. We investigated the possible usefulness of antiestrogenic activity using both in vitro and in vivo models of endometrial function. Using the well-differentiated, hormone-responsive endometrial cell line, ECC-1, PV extract, at concentrations that were not toxic to the cells, significantly reduced alkaline phosphatase activity and cell proliferation in response to estrogen in a dose-dependent manner. The expression of CYR61, an estrogen-induced protein, was blocked in ECC-1 cells by both the antiestrogen ICI 182,780 and PV extract. Interestingly, PV extract did not appear to directly inhibit estrogen signaling. Rather, we found that its activities were probably related to an ability to function as an aryl hydrocarbon receptor (AHR) agonist in ECC-1 cells. In support of this hypothesis, we noted that PV induced CYP1A1, CYP1B1, and AHR repressor expression in a dose-dependent manner–responses that were blocked by small interfering RNA treatment to reduce AHR and specific AHR antagonists. Ovariectomized immunodeficient RAG-2/gamma(c) knockout mice implanted with human endometrial xenografts developed implants only when treated with estrogen. Mice treated with estrogen and PV tea in their drinking water had fewer and smaller xenograft implants compared with their estrogen-treated counterparts that drank only water (P < 0.05). Analysis of the resulting implants by immunohistochemistry demonstrated persistent estrogen receptor (ER), but reduced proliferation and CYR61 expression. Mouse uterine tissue weight in PV-treated mice was not different from controls, and cycle fecundity of intact C57 female mice was unaffected by PV tea treatment. PV, or Self-heal, exhibits significant antiestrogenic properties, both in vitro and in vivo. This activity is likely due to the ability of PV-activated AHR to interfere with estrogen. This herb may be useful as an adjunct for the treatment of estrogen-dependent processes like endometriosis and breast and uterine cancers. Full characterization of this herb will likely provide new insights into the crosstalk between AHR and ESR1, with potential for therapeutic applications in women.

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Biol Reprod. 2009 Feb;80(2):272-8. Epub 2008 Oct 15.

Endometriosis is associated with progesterone resistance in the baboon (Papio anubis) oviduct: evidence based on the localization of oviductal glycoprotein 1 (OVGP1).

Wang C, Mavrogianis PA, Fazleabas AT.

Department of Obstetrics and Gynecology, The People’s Hospital, Beijing University, Beijing 10004, China.

Endometriosis has been associated with a reduced response to progesterone in both the eutopic and ectopic endometrium. In this study we evaluated OVGP1 and steroid receptor expression in oviducts of baboons with endometriosis during the midsecretory phase and determined whether progesterone resistance associated with endometriosis also occurs in the oviduct. Oviducts obtained during the window of uterine receptivity (Day 10 postovulation [PO]) from animals with induced and spontaneous disease were compared to control animals during the proliferative stage and in the implantation window as well as animals treated with the progesterone receptor (PGR) antagonist ZK 137.299 (ZK). OVGP1 was significantly higher in animals with endometriosis compared with Day 10 PO controls and was similar to that seen in the late proliferative phase and in ZK-treated animals. Baboons with spontaneous endometriosis also showed a similar persistence of OVGP1, which was correlated with the maintenance of estrogen receptor 1 (ESR1) in the epithelial cells of animals with endometriosis. However, epithelial cell height and the percentage of ciliation were not affected by endometriosis. These data imply that the normal antagonism of progesterone on ESR and OVGP1, which results in their downregulation during the window of implantation, is absent in animals with endometriosis. This was confirmed further when the action of PGR was antagonized in animals without disease, which also resulted in the persistence of ESR1 and OVGP1. These studies suggest that an aberrant oviductal environment may be an additive factor that contributes to endometriosis-associated infertility.

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J Plast Reconstr Aesthet Surg. 2009 Mar;62(3):420-1. Epub 2008 Oct 11.

Endometriosis following free DIEP breast reconstruction.

McArthur GJ, Lowndes S, Meagher PJ.

Publication Types:

Mol Cell Endocrinol. 2009 Mar 25;301(1-2):212-5. Epub 2008 Sep 19.

The role of the heterocycle in bis(hydroxyphenyl)triazoles for inhibition of 17beta-Hydroxysteroid Dehydrogenase (17beta-HSD) type 1 and type 2.

Al-Soud YA, Bey E, Oster A, Marchais-Oberwinkler S, Werth R, Kruchten P, 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) is responsible for the catalytic reduction of the weak estrogen estrone (E1) into the highly potent 17beta-estradiol (E2). As 17beta-HSD1 is often overexpressed in mammary tumors and endometriosis, the selective inhibition of this enzyme is discussed as a promising approach for the treatment of estrogen-dependent diseases. Recently, we reported on bis(hydroxyphenyl)azoles as a new class of potent inhibitors of 17beta-HSD1. In this paper, we focused on bis(hydroxyphenyl)triazoles. The influence of nitrogens on the potency as well as the space available around the heterocycle was investigated. Substituents were introduced on the triazole core in order to establish additional interactions with the enzyme active site. The compounds were evaluated for activity towards 17beta-HSD1 and selectivity with regard to 17beta-HSD2, the enzyme which is responsible for the deactivation of E2 into E1. 3-[4-(4-Hydroxyphenyl)-1H-1,2,3-triazol-1-yl]phenol (3) was the most active compound discovered in this study with an IC(50) value of 840nM and a reasonable selectivity towards 17beta-HSD2.

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Fertil Steril. 2009 Sep;92(3):868-75. Epub 2008 Oct 1.

Does the learning curve of conservative laparoscopic surgery in women with rectovaginal endometriosis impair the recurrence rate?

Carmona F, Martínez-Zamora A, González X, Ginés A, Buñesch L, Balasch J.

Institut Clínic of Gynecology, Obstetrics and Neonatology, Faculty of Medicine, University of Barcelona, Hospital Clínic-Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

OBJECTIVE: To assess the effect of surgeon’s increasing experience in conservative laparoscopic surgery of women with rectovaginal endometriosis on the surgical outcome of these patients recurrence rate. DESIGN: Prospective cohort study. SETTING: University teaching hospital. PATIENT(S): The first 60 consecutive patients undergoing laparoscopic conservative surgery for symptomatic rectovaginal endometriosis at our institution during a 4- year period. INTERVENTION(S): Cases were classified into two groups according to the date of the patient’s operation: the first 30 cases were defined as the early cases and the subsequent 30 cases as the late cases. MAIN OUTCOME MEASURE(S): Operating time, perioperative complications, and surgical outcome. Univariate and multivariate analyses for risk factors with recurrence of disease. RESULT(S): The two groups were similar in patient characteristics. There was a reduction in the rate of laparoconversion, operating time, estimated amount of blood loss, cases with incomplete removal, and recurrence rate with increasing surgeon’s experience. Surgical completeness was significantly associated with recurrence of disease. CONCLUSION(S): A learning curve is demonstrated in the conservative laparoscopic management of patients with rectovaginal endometriosis. After gaining experience in performing 30 cases, the recurrence rate is significantly reduced.

Fertil Steril. 2009 Mar;91(3):936.e9-11. Epub 2008 Sep 30.

Challenge in the management of endometriosis in the canal of Nuck.

Wang CJ, Chao AS, Wang TH, Wu CT, Chao A, Lai CH.

Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan, Republic of China.

OBJECTIVE: To report a case of endometriosis located at an unusual site in the canal of Nuck. DESIGN: Case report. SETTING: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital. PATIENT(S): A 35-year-old woman with no previous history of surgery had endometriosis in the canal of Nuck excised incompletely via an open skin method. Recurrent endometriosis at the canal of Nuck was noted 9 months later despite postoperative medical treatment. INTERVENTION(S): Laparoscopic surgery and open skin method. MAIN OUTCOME MEASURE(S): Removal of endometriosis in the canal of Nuck and repair of the inguinal ring. RESULT(S): The patent left canal of Nuck identified, endometriosis completely resected, and the inguinal ring closed. She was well 12 months after the second surgery. CONCLUSION(S): We suggest that when encountering endometriosis in the canal of Nuck, removing all involved lesions and closing of the internal inguinal ring is indicated.

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Biol Reprod. 2009 Jan;80(1):105-14. Epub 2008 Sep 24.

Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis.

Aghajanova L, Hamilton A, Kwintkiewicz J, Vo KC, Giudice LC.

Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143, USA.

Identification of mechanisms underlying endometriosis pathogenesis will facilitate understanding and treatment of infertility and pain associated with this disorder. Herein, we investigated the expression of steroidogenic pathway enzymes and key decidualization biomarkers in endometrial tissue and in eutopic endometrial stromal fibroblasts (hESFs) from women with vs. those without endometriosis, and subsequently treated in vitro with 8-bromo-cAMP (8-Br-cAMP) or progesterone (P4). Real-time quantitative PCR, immunohistochemistry, ELISA, and radiometric aromatase activity assay were used. The results demonstrate significantly increased (14.5-fold; P=0.037) expression of aromatase in eutopic endometrium of women with disease. In 8-Br-cAMP-treated hESF from eutopic endometrium of women with endometriosis, the balance in estradiol (E2) and P4 biosynthetic and metabolizing enzymes is disturbed (decreased HSD3B1 and HSD17B2, and increased HSD17B1 and aromatase), with the equilibrium being shifted towards an E2-enriched milieu. However, hESF from the same group of women treated with P4 did not demonstrate such responsiveness. Lower expression of IGFBP1 and prolactin mRNA and protein was observed in hESF from women with vs. those without endometriosis in response to 8-Br-cAMP, but not P4, suggesting a blunted response of these decidual biomarkers to activation of the PKA pathway in eutopic endometrium in women with disease. The dichotomy of 8-Br-cAMP regulation of select steroidogenic enzymes leading to an enriched E2 milieu within the endometrium and a blunted response of decidual biomarkers to this decidualizing agent of hESF from women with endometriosis suggests resistance to full decidualization of the stromal fibroblasts and mechanisms underlying implantation failure and the pathophysiology of this disorder.

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Hum Reprod Update. 2009 Jan-Feb;15(1):97-118. Epub 2008 Sep 19.

Functional genetic polymorphisms and female reproductive disorders: part II–endometriosis.

Tempfer CB, Simoni M, Destenaves B, Fauser BC.

Department of Obstetrics and Gynecology, Medical University, Vienna, Austria.

BACKGROUND: Endometriosis has a strong genetic component, and numerous genetic studies have been reported. METHODS: We have systematically reviewed these studies and included 114 in our final selection. RESULTS: We found no consistent evidence linking endometriosis with specific polymorphisms in genes encoding inflammatory mediators, proteins involved in sex steroid metabolism, vascular function and tissue remodelling. Although a number of polymorphisms have been associated with endometriosis in selected populations, the associations have not been independently confirmed, either because only single studies were carried out on these markers/genes or because other studies reported no association. The most solid evidence linking specific polymorphisms to endometriosis came from studies investigating glutathione-S-transferase, a phase II detoxification enzyme. Carriage of the GSTT1 null deletion variant showed consistent association with endometriosis with a 29% increased risk; however, it cannot be excluded that this result was due to publication bias, and this association should be independently confirmed in large-scale, well-designed case-control studies. CONCLUSIONS: The evidence of an association between genetic polymorphisms and endometriosis is weak. Carriage of the GSTT1 null deletion may moderately increase the risk of this disease. We suggest that the methodology of association studies should be improved in order to identify and validate associations in endometriosis.

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Fertil Steril. 2009 Jul;92(1):328-43. Epub 2008 Sep 18.

Melatonin and the ovary: physiological and pathophysiological implications.

Tamura H, Nakamura Y, Korkmaz A, Manchester LC, Tan DX, Sugino N, Reiter RJ.

Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

OBJECTIVE: To summarize the role of melatonin in the physiology and pathophysiology of the ovary. DESIGN: Review of literature. SETTING: University Health Science Center. RESULT(S): Melatonin plays an essential role in the pathogenesis of many reproductive processes. Human preovulatory follicular fluid (FF) contains higher concentrations of melatonin than does plasma, and melatonin receptors are present in ovarian granulosa cells (GC). Melatonin has been shown to have direct effects on ovarian function. Reactive oxygen species and apoptosis are involved in a number of reproductive events including folliculogenesis, follicular atresia, ovulation, oocyte maturation, and corpus luteum (CL) formation. Melatonin and its metabolites are powerful antioxidants; the primitive and primary function of melatonin may be its actions as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. A large amount of scientific evidence supports a local role of melatonin in the human reproductive processes. The indole also has potential roles in the pathophysiology of endometriosis, polycystic ovary syndrome (PCOS), and premature ovarian failure (POF). CONCLUSION(S): We summarize the current understanding of melatonin’s essential functions in the human ovary. Melatonin could become an important medication for improving ovarian function and oocyte quality, and open new opportunities for the management of several ovarian diseases.

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Photomed Laser Surg. 2009 Apr;27(2):325-35.

Autofluorescence of normal, benign, and malignant ovarian tissues: a pilot study.

Kamath SD, Bhat RA, Ray S, Mahato KK.

Division of Laser Spectroscopy, Manipal Life Sciences Centre, Kasturba Medical College, Manipal University, Manipal, India.

OBJECTIVE: The objective of this study is to evaluate the efficacy of laser-induced fluorescence (LIF) data obtained at 325-nm pulsed laser excitation for the discrimination of normal, benign, and malignant ovarian tissues. BACKGROUND DATA: Several studies have reported that the autofluorescence technique has a high specificity and sensitivity for discrimination between diseased and non-diseased tissues of various cancers, and also has the advantages of being non-invasive and producing a real-time diagnosis. When using this technique on ovarian tissues in most of the previously reported studies, multivariate statistical tools were used and classification analyses were carried out. MATERIALS AND METHODS: Autofluorescence spectra of normal, benign, and malignant ovarian tissues were recorded with 325-nm pulsed laser excitation in the spectral region from 350-600 nm in vitro. The spectral analysis for discrimination between the different types of tissues was carried out using principal component analysis (PCA)-based non-parametric k-nearest neighbor (k-NN) analysis. RESULTS: A total of 97 (34 normal, 33 benign, and 30 malignant) spectra were obtained from 22 subjects with normal, benign, and malignant tissues. The discrimination analysis of data using a PCA-based k-NN algorithm showed very good discrimination. The performance of the analysis was evaluated by calculating statistical parameters, specificity, sensitivity, and accuracy and were found to be 100%, 90.90%, and 94.2%, respectively. CONCLUSION: The results show that the discrimination of normal, benign, and malignant ovarian conditions can be achieved quite successfully using LIF.

Publication Types:

Biol Reprod. 2009 Jan;80(1):79-85. Epub 2008 Sep 17.

Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium.

Lee B, Du H, Taylor HS.

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

The eutopic endometrium in women with endometriosis demonstrates diminished endometrial receptivity and altered gene expression. It is unknown if the endometrium being defective gives rise to a predisposition toward endometriosis and infertility or, alternatively, if endometriosis causes the altered endometrial receptivity. Here we created experimental endometriosis in mice and examined the expression of several markers of endometrial receptivity in the eutopic endometrium. Methylation of Hoxa10 was also evaluated as a potential mechanism responsible for altered gene expression. Expression of each gene was measured using quantitative real-time RT-PCR at 14 wk after induction of endometriosis. Expression of Hoxa10 and Hoxa11, which are necessary for endometrial receptivity, were decreased in the endometriosis group. Insulin-like growth factor binding protein-1 (Igfbp1) mRNA was decreased in the endometriosis group. However, there was no change in Integrin beta3 (Itgb3) mRNA expression. Total progesterone receptor (Pgr-AB) was increased in the endometriosis group and the ratio of Pgr-B to Pgr-AB was increased, indicating a shift from Pgr-A to Pgr-B expression. Basic transcription element-binding protein-1 (Bteb1), official symbol and name Klf9, Kruppel-like factor 9, which functionally interacts with Pgr in endometrium, was also decreased in the endometriosis group. In addition, hypermethylation of Hoxa10 in the endometriosis group was shown by methylation-specific PCR and confirmed by bisulfite sequencing. These findings demonstrate that normal endometrium, when placed in an ectopic location to create experimental endometriosis, led to characteristic changes in gene expression in eutopic endometrium. These data suggest the existence of a signal conduction pathway from endometriosis that alters endometrial gene expression through altered Pgr signaling and epigenetic programming.

Publication Types:

Arch Gynecol Obstet. 2009 May;279(5):729-31. Epub 2008 Sep 16.

Xanthogranulomatous inflammation: a rare cause of premature ovarian failure.

Singh N, Dadhwal V, Sharma KA, Mittal S.

Department of Obstetrics and Gynaecology, All India Institute Institute of Medical Sciences, New Delhi, India.

Xanthogranulomatous inflammation is rare, mainly involving the kidneys, histologically characterized by partial or complete replacement of the mucosa by granulation tissue with an abundance of foamy histiocytes, siderophages and multinucleated giant cells. We report an unusual presentation of xanthogranulomatous inflammation of the genital tract in a young female presenting with premature ovarian failure. A 25-year-old unmarried female presented to the gynecology OPD with amenorrhea and lump abdomen for one and half years with weight loss and mucoid discharge per rectum for 2 months. On investigating, CECT showed a heterogeneously enhancing mass lesion with solid cystic components in pelvis. Cystic components showed enhancing walls and air fluid levels. Uterus and ovaries were not seen separately. There were multiple lymph nodes in retroperitoneum. Both LH and FSH were raised to post menopausal levels (FSH-69.35, LH-64.53). A provisional diagnosis of ovarian malignancy was made and a differential diagnosis of genital tuberculosis was kept and a decision for laparotomy was taken. Intraoperatively, there was a mass arising from the right side of fundus stuck to rectum. There was a pus pocket in the tumor. The final histopathological report was suggestive of endometrioma with xanthogranulomatous inflammation involving adjacent ovary and fallopian tube.

Publication Types:

Photomed Laser Surg. 2009 Apr;27(2):295-301.

5-aminolevulinic acid-mediated photodynamic therapy of human endometriotic primary epithelial cells.

Wolun-Cholewa M, Butowska W, Fischer N, Warcho W, Nowak-Markwitz E.

Department of Cell Biology, University of Medical Sciences, Poznan, Poland.

OBJECTIVE: Despite progress in medicine, appropriate diagnosis and treatment of endometriosis poses a serious problem. For this reason, in in-vitro experiments were performed on a potential method of employing photodynamic therapy (PDT) of endometriosis using 5-aminolevulinic acid (ALA). BACKGROUND DATA: The exogenous application of ALA induces the accumulation of protoporphyrin IX, a natural and effective photosensitizer used in photodynamic diagnosis and therapy. MATERIALS AND METHODS: To this end primary epithelial cells were isolated from endometriotic foci, preincubated with various ALA concentrations, and then exposed to light energy (a bulb or laser) for 8 min; 24 and 48 h later cell lesions were evaluated using fluorescent staining. RESULTS: When bulb illumination was used, after 48 h cells were found that had disturbed chromatin concentration and fragmentation. Illumination with a laser beam resulted in strong induction of apoptosis 24 h post-exposure. With both types of illumination the number of necrotic cells was insignificant. Staining with rhodamine 123 demonstrated the presence within the endometriotic foci of epithelial cells that were resistant to ALA-induced photodynamic therapy. CONCLUSION: The effects of PDT on primary epithelial endometriotic cells may prove useful in designing a phototherapeutic procedure for the detection and treatment of endometriosis.

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Arch Gynecol Obstet. 2009 May;279(5):613-9. Epub 2008 Sep 6.

The role of urocortin in gynecological and obstetrical conditions.

Iavazzo C, Baka S, Malamitsi-Puchner A.

2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, University of Athens, Athens, Greece.

AIM: The objective of the review is to present the possible role of urocortin, a novel peptide of the corticotrophin releasing factor family, in different conditions of obstetrics and gynecology such as preterm labor, preeclampsia or ovarian steroidogenesis. METHOD-RESULTS: A MEDLINE search was commenced with the terms “urocortin”, “preterm labor”, “preeclampsia”, “ovary”, “endometrium”, “myometrium”, “placenta”, “plasma”, “amniotic fluid”. Seventy-three articles were found to be relevant on the field and the potential role of urocortin in such conditions is presented. CONCLUSION: Amounting data suggest that urocortin could play a significant role in human reproduction (steroidogenesis in the ovary, maintenance of the placental function and labor). Further investigation on the field is necessary in order to clarify the natural role of this newly identified molecule in the field of obstetrics and gynecology.

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Theriogenology. 2009 Jan 15;71(2):264-74. Epub 2008 Aug 31.

Immunohistochemical and histochemical identification of proteins and carbohydrates in the equine endometrium Expression patterns for mares suffering from endometrosis.

Hoffmann C, Bazer FW, Klug J, Aupperle H, Ellenberger C, Schoon HA.

Institute of Veterinary Pathology of the Faculty of Veterinary Medicine, University of Leipzig, An den Tierkliniken 33, 04103 Leipzig, Germany.

Although alterations in patterns of protein secretion revealed in uterine flushings from mares suffering from endometrosis have been described, little is known about alterations at the cellular level. Hence, the aim of this study was to characterize deviations in patterns of uterine gland secretion patterns using endometrial biopsies, histochemical and newly established immunohistochemical methods. Forty-eight endometrial biopsies were obtained from mares suffering from various types of endometrosis (active and inactive, destructive and non-destructive) and degree (mild to severe) were analyzed for expression of the proteins uteroglobin, uteroferrin, calbindinD9k and uterocalin as representatives of endometrial proteins detectable by immunohistochemistry using polyclonal antibodies. Glycogen was identified using the PAS-reaction and mucopolysaccharides were stained with alcian blue. Uterine glandular epithelia within fibrotic foci mostly revealed a protein and carbohydrate pattern of expression which was independent of hormonal changes during the estrous cycle. In comparison to non-affected glands, most epithelial cells within periglandular fibrosis exhibited decreased immunostaining intensity for proteins, especially when there was destructive endometrosis. However, uteroferrin staining intensity was strong within areas of severe destructive endometrosis. Moreover, only few basal glandular epithelial cells, especially those in cystic glands, stained for mucopolysaccharides that are typically seen within the luminal epithelia. Usually a single fibrotic focus caused only slight alterations in glandular proteins and carbohydrate reaction patterns, so that only more severe endometrosis lead to deviations which were detectable in uterine flushings. The highly sensitive methods used in the present study allow studies of uterine secretion patterns in the context of routine assessment of endometrial biopsies.

Mol Cell Endocrinol. 2009 Mar 25;301(1-2):59-64. Epub 2008 Aug 13.

Disturbed estrogen and progesterone action in ovarian endometriosis.

Smuc T, Hevir N, Ribic-Pucelj M, Husen B, Thole H, Rizner TL.

Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.

Endometriosis is a very common disease in pre-menopausal women, where defective metabolism of steroid hormones plays an important role in its development and promotion. In the present study, we have examined the expression of 11 estrogen and progesterone metabolizing enzymes and their corresponding receptors in samples of ovarian endometriomas and control endometrium. Expression analysis revealed significant up-regulation of enzymes involved in estradiol formation (aromatase, sulfatase and all reductive 17beta-hydroxysteroid dehydrogenases) and in progesterone inactivation (AKR1C1 and AKR1C3). Among the estrogen and progesterone receptors, ERalpha was down-regulated, ERbeta was up-regulated, and there was no significant difference in expression of progesterone receptors A and B (PRAB). Our data indicate that several enzymes of estrogen and progesterone metabolism are aberrantly expressed in endometriosis, which can lead to increased local levels of mitogenic estradiol and decreased levels of protective progesterone. Changes in estrogen receptor expression suggest that estradiol may also act via non-estrogen receptor-mediated pathways, while expression of progesterone receptors still needs further investigation.

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Fertil Steril. 2009 Aug;92(2):471-80. Epub 2008 Aug 22.

Laparoscopy in women with unexplained infertility: a cost-effectiveness analysis.

Moayeri SE, Lee HC, Lathi RB, Westphal LM, Milki AA, Garber AM.

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Stanford University, Stanford, California, USA.

OBJECTIVE: To evaluate the cost effectiveness of laparoscopy for unexplained infertility. DESIGN: We performed a cost-effectiveness analysis using a computer-generated decision analysis tree. Data used to construct the mathematical model were extracted from the literature or obtained from our practice. We compared outcomes following four treatment strategies: [1] no treatment, [2] standard infertility treatment algorithm (SITA), [3] laparoscopy with expectant management (LSC/EM), and [4] laparoscopy with infertility therapy (LSC/IT). The incremental cost-effectiveness ratio (ICER) was calculated, and one-way sensitivity analyses assessed the impact of varying base-case estimates. SETTING: Academic in vitro fertilization practice. PATIENT(S): Computer-simulated patients assigned to one of four treatments. INTERVENTION(S): Fertility treatment or laparoscopy. MAIN OUTCOME MEASURE(S): Incremental cost-effectiveness ratios. RESULT(S): Using base-case assumptions, LSC/EM was preferred (ICER =$128,400 per live-birth in U.S. dollars). Changing the following did not alter results: rates and costs of multiple gestations, penalty for high-order multiples, infertility treatment costs, and endometriosis prevalence. Outcomes were most affected by patient dropout from infertility treatments-SITA was preferred when dropout was less than 9% per cycle. Less important factors included surgical costs, acceptability of twins, and the effects of untreated endometriosis on fecundity. CONCLUSION(S): Laparoscopy is cost effective in the initial management of young women with infertility, particularly when infertility treatment dropout rates exceed 9% per cycle.

Fertil Steril. 2009 May;91(5 Suppl):2199-209. Epub 2008 Aug 22.

Induction of peritoneal endometriosis in nude mice with use of human immortalized endometriosis epithelial and stromal cells: a potential experimental tool to study molecular pathogenesis of endometriosis in humans.

Banu SK, Starzinski-Powitz A, Speights VO, Burghardt RC, Arosh JA.

Reproductive Endocrinology and Cell Signaling Laboratory, Department of Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas 77843, USA.

OBJECTIVE: To determine whether a mixed population of immortalized human endometriosis epithelial and stromal cells is able to induce peritoneal endometriosis in nude mice. DESIGN: Prospective experimental study. Human immortalized endometriosis epithelial and stromal cells were xenografted into ovariectomized nude mice. Macroscopically, the number of induced endometriosis-like lesions and their color were determined. Microscopically, histomorphology of endometriosis glands and their structure were analyzed, and comparisons were made with tissue from spontaneous endometriosis in women. SETTING: College of Veterinary Medicine and Biomedical Sciences, Texas A&M University. ANIMALS: Seven ovariectomized nude mice. INTERVENTION(S): Minimal invasive procedures were performed to administer estrogen pellets and transplant immortalized human endometriosis epithelial and stromal cells into nude mice. MAIN OUTCOME MEASURE(S): Peritoneal endometriosis-like lesions induced in nude mice were characterized and compared with spontaneous peritoneal endometriosis in women. RESULT(S): Xenografts of human immortalized endometriosis epithelial and stromal cells into the peritoneal cavity of the recipient nude mice are able to proliferate, attach, invade, reorganize, and establish peritoneal endometriosis. Endometriosis glands at different stages of growth were present in induced endometriosis-like lesions. Proliferating cell nuclear antigen, metalloproteinase 2, estrogen receptor-alpha, cyclooxygenase-2, and prostaglandin E(2) receptors EP2 and EP4 proteins were expressed in both endometriosis glandular epithelial and stromal cells of the induced endometriosis-like lesions. CONCLUSION(S): This xenograft model could be used as a potential experimental tool to understand the molecular and cellular aspects of the pathogenesis of endometriosis in humans.

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Fertil Steril. 2009 Apr;91(4 Suppl):1441-4. Epub 2008 Aug 22.

Wilms’ tumor gene 1 (WT1) overexpression in neurons in deep endometriosis: a pilot study.

Coosemans A, Moerman P, Vergote I, Koninckx PR, Van Gool SW, Amant F.

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

Innervation of deep endometriosis has recently been linked to its severe pain symptoms. We demonstrated for the first time that the Wilms’ tumor gene 1 is overexpressed in part of these nerves.

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Fertil Steril. 2009 May;91(5 Suppl):2148-56. Epub 2008 Aug 16.

Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin- 1 beta in ectopic endometrial cells.

Veillat V, Lavoie CH, Metz CN, Roger T, Labelle Y, Akoum A.

Unité d’Endocrinologie de la Reproduction, Centre de Recherche, Hôpital Saint-François d’Assise, Centre Hospitalier Universitaire de Québec, Faculté de Médecine, Université Laval, Québec, Canada.

OBJECTIVE: To investigate the involvement of the nuclear factor (NF)-kappaB in the interleukin (IL)-1 beta-mediated macrophage migration inhibitory factor (MIF) gene activation. DESIGN: Prospective study. SETTING: Human reproduction research laboratory. PATIENT(S): Nine women with endometriotic lesions. INTERVENTION(S): Endometriotic lesions were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S): The MIF protein secretion was analyzed by ELISA, MIF mRNA expression by quantitative real-time polymerase chain reaction (PCR), NF-kappaB translocation into the nucleus by electrophoresis mobility shift assay, I kappaB phosphorylation and degradation by Western blot, and human MIF promoter activity by transient cell transfection. RESULT(S): This study showed a significant dose-dependent increase of MIF protein secretion and mRNA expression, the NF-kappaB translocation into the nucleus, I kappaB phosphorylation, I kappaB degradation, and human MIF promoter activity in endometriotic stromal cells in response to IL-1 beta. Curcumin (NF-kappaB inhibitor) significantly inhibited all these IL-1 beta-mediated effects. Analysis of the activity of deletion constructs of the human MIF promoter and a computer search localized two putative regulatory elements corresponding to NF-kappaB binding sites at positions -2538/-2528 bp and -1389/-1380 bp. CONCLUSION(S): This study suggests the involvement of the nuclear transcription factor NF-kappaB in MIF gene activation in ectopic endometrial cells in response to IL-1 beta and identifies a possible pathway of endometriosis-associated inflammation and ectopic cell growth.

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